EP1682076A4 - Inhibitors of coronavirus protease and methods of use thereof - Google Patents

Inhibitors of coronavirus protease and methods of use thereof

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Publication number
EP1682076A4
EP1682076A4 EP04816955A EP04816955A EP1682076A4 EP 1682076 A4 EP1682076 A4 EP 1682076A4 EP 04816955 A EP04816955 A EP 04816955A EP 04816955 A EP04816955 A EP 04816955A EP 1682076 A4 EP1682076 A4 EP 1682076A4
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EP
European Patent Office
Prior art keywords
alkyl
hydrogen
independently
benzyl
alkene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP04816955A
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German (de)
French (fr)
Other versions
EP1682076A2 (en
Inventor
Ernesto Freire
Raphael Ottenbrite
Yingxin Xiao
Adrian Velazquez-Campoy
Stephanie Leavitt
Usman Bacha
Jennifer Barrila
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Johns Hopkins University
Fulcrum Pharmaceuticals Inc
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Johns Hopkins University
Fulcrum Pharmaceuticals Inc
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Application filed by Johns Hopkins University, Fulcrum Pharmaceuticals Inc filed Critical Johns Hopkins University
Publication of EP1682076A2 publication Critical patent/EP1682076A2/en
Publication of EP1682076A4 publication Critical patent/EP1682076A4/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to boron-containing compounds that are inhibitors of coronavirus protease and methods of use thereof.
  • Severe Acute Respiratory Syndrome The first cases of Severe Acute Respiratory Syndrome (SARS) appeared at the end of 2002 in Southern China. By May 2003, SARS had spread to other continents through international travel. It is estimated by the World Health Organization that a total of 15,000 people were infected during the outbreak with an average mortality rate of 15 % . The actual mortality rate appears to depend on the age of the patient. The fatality ratio is estimated to be less than 1% in persons aged 24 years or younger, 6% in persons aged 25 to 44 years, 15% in persons aged 45 to 64 years, and greater than 50% in persons aged 65 years and older.
  • SARS patients typically have high fever, malaise, rigor, headache and nonproductive cough or dyspnea and may progress to generalized interstitial infiltrated in the lung, requiring incubation and mechanical ventilation.
  • the causative agent of SARs is a coronavirus never before seen in humans.
  • the genome of the SARS-associated coronavirus has been sequenced.
  • the genome sequence of the SARS-associated coronavirus reveals that the virus does not belong to any of the known groups of coronaviruses, including two human coronaviruses, HCoN-OC43 and HCoN-229E (Drosten et al. , Identification of a Novel Coronavirus in Patients with Severe Acute Respiratory Syndrome. N. Engl. J. Med.
  • SARS-associated coronavirus genome appears to be closer to the murine, bovine, porcine, and human coronaviruses in Group II and avian coronavirus IBN in Group I (Marra et al.,. Science 300:1399-404 (2003)). At present, no effective therapy is available for the treatment of SARS.
  • m-(Dansylamidophenyl)- boronic acid has also been reported to be a submicromolar inhibitor of the Enterobacter cloacae P99 ⁇ -lactamase (Dryjanski et al , Biochemistiy, 34, 3561-3568 (1995)).
  • Strynadka and colleagues used the crystallographic structure of a mutant TEM- 1 enzyme-penicillin G complex to design a novel alkylboronic acid inhibitor [(1R)-1- acetamido-2-(3-carboxyphenyl)ethane boronic acid] with high affinity for this enzyme. (Strynadka et al, Nat. Struc. Biol. , 3, 688-695 (1996)).
  • boronic-acids are known and used as ⁇ -lactamase inhibitors, (e.g. , Tondi et al., Chemistry & Biology, 8, 593-610 (2001); Martin et al., Bioorganic & Medicinal Chemistry Letters, 4(10), 1229- 1234 (1994); Weston et al., J. Med. Chem. , 41, 4577-4586 (1998); U.S. Patents No. 6,075,014 and 6,184,363; and U.S. Provisional Patent Application Serial No. 60/477,636, filed June 10, 2003, and co-pending U.S. patent application serial no. 10/866,179, filed June 10, 2004, both entitled "Beta-Lactamase Inhibitors and Methods of Use Thereof". No boron-containing compounds have been reported as inhibitors of coronavirus protease inhibitors.
  • the present invention relates to boron-containing compounds.
  • such compounds are boric acid and boronic acids.
  • such compounds are organic boron-containing compounds.
  • the compounds are described by formula (1):
  • the invention also provides a method of inhibiting coronavirus protease(s), particularly coronavirus protease(s) that has one or more serine or threonine residue(s) at or near its active site, more particularly protease of SARS-associated coronavirus.
  • the method comprises contacting the protease(s) with an effective amount of one or more boron-containing compounds, particularly compounds of formulae (1)-(15).
  • the invention additionally provides a method of treating infections caused by coronavirus, particularly by coronavirus that has protease(s) with one or more serine or threonine residue(s) at or near the protease active site, more particularly by SARS- associated coronavirus.
  • Such method comprises administering to a subject suffering from such infections an effective amount of one or more boron-containing compounds, particularly compounds of formulae (1)-(15).
  • the invention further provides a method of detecting coronavirus, particularly coronavirus that has protease(s) with one or more serine or threonine residue(s) at or near the protease active site, more particularly by SARS-associated coronavirus.
  • Such method comprises contacting the testing sample obtained from a patient with boron- containing compounds of formulae (1)-(15) that have been (1) tethered to an appropriate surface such that protease that becomes in contact and bound to the tethered compound can be detected; (2) labeled by fluorescent, radioactive or other markers that allow identification of coronavirus protease bound to the compound; or (3) that by any other mean can be used to detect the presence of coronavirus protease.
  • the invention also provides a pharmaceutical composition comprising one or more boron-containing compounds, particularly compounds of formulae (1)-(15), and a pharmaceutically acceptable carrier.
  • Fig. 1. shows a sequence alignment of identified SARS-associated coronavirus protease and the MHV protease. Identities are shown in dark grey and similarities in light grey.
  • Fig. 2. shows an alignment of sequences around the serine cluster for sequences identified by BLAST search with SARS-associated coronavirus protease 3CL pro .
  • the 3CL pro coding is shown in Fig. 1 and in SEQ ID NO: 1.
  • the highest homology was found with the mouse hepatitis coronavirus picorna 3C-like endopeptidase [MER02029 ] (MHN Protease) [SEQ ID NO: 2].
  • the alignment of the two sequences is shown in Fig. 1.
  • the sequences of the two enzymes are 50% identical (dark grey in Fig. 1) and ' 72% similar (dark grey and light grey in Fig. 1).
  • cysteine proteases are characterized by a catalytic cysteine (Cys 145) and histidine (His 41) and therefore are classified as cysteine proteases since the nucleophilic catalytic residue is a cysteine.
  • cysteine proteases are essential to the viral reproductive cycle since they are involved in the processing of all downstream domains of the replicase polyproteins of these viruses (Ziebuhr et al. , (2000). Virus-encoded proteinases and proteolytic processing in the Nidovirales. J. Gen. Virol. 81, 853-879). For this reason, inhibition of this enzyme has been shown to inhibit viral replication in mouse hepatitis virus (MHV) infected cells (Kim et al., (1995).
  • MHV hepatitis virus
  • Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology 208, 1-8).
  • the cleavage sites for the 3C-like viral proteases that have been studied are highly conserved, the PI site being exclusively occupied by Gin and the PI' site by small aliphatic residues (Ser, Ala, Asn, Gly, Cys).
  • the crystallographic structure of the SARS-associated coronavirus CL3 pro protease is available in the public protein database (accession code lq2w). Analysis of the active site of the protease reveals a cluster of serines (Ser 139, Ser 144 and Ser 147).
  • the serine cluster in the SARS-associated coronavirus protease 3CL pro is highly conserved in similar proteins from other coronavirus indicating that either the same compound or similar compounds can be used to target this region of the binding site and inhibit these proteases.
  • the entire region is highly conserved opening the possibility for wide spectrum antivirals targeting this region of the protease.
  • Fig. 2 shows the sequence alignments between residues 121 and 160 for the proteases of twenty different coronaviruses. conserveed serine residues being targeted are boxed.
  • SARS-HCN severe acute respiratory syndrome-human coronavirus
  • MHV ML-10 murine hepatitis virus strain ML-10
  • AAF69341 [SEQ ID NO: 4]; MHV A59 (murine hepatitis virus strain A59): NP_740610 [SEQ ID NO: 5]; MHV JHM (murine hepatitis virus strain JHM): P19751 [SEQ ID NO: 6]; MHV-2 (murine hepatitis virus strain 2): AAF19383 [SEQ ID NO: 7]; MHV Penn 97-1 (murine hepatitis virus strain Penn 97-1): AAF69331 [SEQ ID NO: 8]; MHV ML- 11 (murine hepatitis virus strain ML-11): AAF68919 [SEQ ID NO: 9]; BCV Quebec (bovine coronavirus strain Quebec): AAL40396 [SEQ ID NO: 10]; BCV LUN (bovine coronavirus strain LUN): AAL57315 [SEQ ID NO: 11]; BCV Mebus (bovine coronavirus
  • serine or threonine particularly serine cluster, threonine cluster, and serine/threonine cluster, are chosen as a prime target site because the OH groups in serine and threonine residues are highly reactive with boron-containing compounds, particularly boric acid and boronic acids.
  • coronavirus proteases such as SARS-associated coronavirus protease 3CL pro contains a cluster of two or more serines and/or threonines (SARS-associated coronavirus protease contains a cluster of three serines)
  • multifunctional boron-containing compounds i.e., a compound containing two or more boron atoms
  • multifunctional boronic acids i.e., a compound containing two or more
  • the boron-containing compounds of the present invention can be organic compounds that contain boron.
  • Non-limiting examples of such boron-containing compounds include arylboronic acid, arylborates, arylboranes, alkylboronic acids, alkyl borates, alkylboranes and boron heterocyclics, and boron-containing compounds disclosed in Koehler et ah, Biochemistry 10, 2477- 2483 (1971); Kiener et al., Biochem. J.
  • the compound of the present invention is a compound described by formula (A) HO B OH (A) T wherein Tt comprises a ring structure or any other organic functional group; and B is boron.
  • Non-limiting examples of Ti include cycloalkyl, cyclic alkene or heterocyclic alkene with one or more substituents R.
  • the compound of the present invention is a compound described by formula (B)
  • Ti and T 3 each comprises a ring structure or any other organic functional group; and T 2 is a linker; and B is boron.
  • Ti and T 3 include cycloalkyl, cyclic alkene or heterocyclic alkene with one or more substituents R.
  • R independently represents any group, non-limiting examples include hydrogen, O- 6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, t ' -
  • Non-limiting examples of cyclic alkene include, benzene, naphthalene, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, indene, fluorene, anthracene and phenanthrene.
  • heterocyclic alkene examples include, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, triazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, benzofuran, thionaphtene, indole, dibenzofuran, dibenzothiophene, carbazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, coumarin, quinoline, isoquinoline, acridine, phenothiazine and phenazine.
  • the compound of the present invention is a multifunctional boron-containing compound (i.e., a compound containing two or more boron atoms).
  • the compound of the present invention is a multifunctional boronic acid (i.e., a compound containing two or more -B(OH)2 groups).
  • Tables 1-15 which set forth without limitation representative compounds 1-403. In all cases, when a compound no. is listed in more than row of tables 1-15, it is to be understood that all of the substituents listed for a given compound no. are found together on a single compound.
  • Ri through Rs, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri through Rt each independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, C alkoxy (e.g., n-butoxy, z-butoxy, .sec-butoxy), RwRisN- (wherein R ⁇ 4 and R15 are each independently hydrogen or C1-6 alkyl), R ⁇ 4 Ri5Ri ⁇ N + G ⁇ (wherein Rw, R15 and Ri6 are each independently hydrogen, Ci- ⁇ alkyl or benzyl, G represents halogen, SO 4 or BF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen cyano, borono, nitro, carboxyl, Ci- ⁇ alkylcarboxyl, Ci- ⁇ alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, dipheny
  • R19 and R20 each independently represents a hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
  • R> through Rs each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl;
  • m and n are each independently 0, 1, or 2;
  • X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, - CO-O-,
  • -C(OH) NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or G-e alkyl), -O(CH 2 )kORi8- (wherein Ris is hydrogen or Ci-e alkyl, and k is 1, 2 or 3), -CONR19OH or
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, Ci- ⁇ alkoxy, RwRisN- (wherein R ⁇ 4 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), Ri 4 RisRi6N + G " (wherein R ⁇ 4 , R15 and Ri ⁇ are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci- ⁇ alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phen
  • R19 through R21 each independently represents a hydrogen, Ci- ⁇ alkyl, trifluoromethyl or benzyl
  • Rs through Rs each independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl
  • m and n are each independently 0 or 1
  • R> represents Ci- ⁇ alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, C1-6 alkyl, R14R15N- (wherein R ⁇ 4 and R15 are each independently hydrogen or Ci- ⁇ alkyl), R ⁇ 4 R ⁇ sRi6N + G " (wherein Rw, R15 and Ri6 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, hal
  • R19 through R21 each independently represents a hydrogen, Ci- ⁇ alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents Ci- ⁇ alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, Cw alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), - NRi9OH(wherein R19 represents a hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N- (wherein R ⁇
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri through Rt each independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N- (wherein Rw and R15 are each independently hydrogen or C ⁇ -e alkyl), Rt 4 Ri5Ri6N + G ⁇ (wherein R14, R15 and Ri6 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci- ⁇ alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t
  • Rn is hydrogen or C1-6 alkyl
  • -O(CH2)kOR ⁇ s- wherein Ri8 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3
  • -CONR19OH or - CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • Rs through Rs each independently represents hydrogen, Ci-e alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl
  • m and n are each independently 0, 1, or 2
  • X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -
  • NRi9OH (wherein R19 represents a hydrogen, C1-6 alkyl, G3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein R14 and R15 are each independently hydrogen, hydroxyl or O- ⁇ alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C ⁇ -6 alkyl, C3-7 cycloalkyl, Ci- ⁇ alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein R14 and R15 are each independently hydrogen or Ci- ⁇ alkyl), Ri4Ri5Ri ⁇ N + G ⁇ (wherein Rw, R15 and Ri6 are each independently
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d.
  • R9 represents Ci- ⁇ alkyl, C 3- 7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio]
  • a C5-7 cycloalkane a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio
  • each Rio independently represents hydrogen, Ci- ⁇ alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or C1-6 alkyl), RuR ⁇ sRi6N + G ⁇ (wherein Ru, Ris and Ri ⁇ are each independently hydrogen, Ci-e alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, halogen
  • R19 through R21 each independently represents a hydrogen, Ci- ⁇ alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C 3 -7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13
  • R12 represents hydroxyl, Ci- ⁇ alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), - NRi9OH(wherein R19 represents a hydrogen, C ⁇ -6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw
  • each cyclic alkene is independently a structure contaimng 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (1) are set forth in Table 1 below.
  • a most preferred compounds in Formula (1) is HO_excellentOH tf- FL-103
  • Rt through Rs, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri through Rt each independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and R15 are each independently hydrogen or C1-6 alkyl), RwR ⁇ sRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, Ci-e alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci- ⁇ alkylcarboxyl, Ci- ⁇ alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-Z
  • R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents Ci- ⁇ alkyl,
  • -C(OH) NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-e alkyl), -O(CH2)kOR ⁇ s- (wherein Ris is hydrogen or Ci- ⁇ alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH( wherein R19 through R21 each independently represents a hydrogen, Ci- e alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl).
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • -NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N N-;
  • R19 through R2i each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents Ci- ⁇ alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, C alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci- ⁇ alkoxy
  • Rn is hydrogen or CM alkyl
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form O3-7 cycloalkyl
  • m and n are each independently 0, 1, or 2
  • X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO- O-,
  • R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherem the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio]
  • a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio
  • each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi
  • R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
  • Q represents -CH2CHRuCORi2 ⁇ r -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRis
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d.
  • R> represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each mdependently hydrogen or CM alkyl), RwRi5Ri ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen
  • R19 through R21 each independently represents a hydrogen, Ci- ⁇ alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic atkene may be substituted with one or more substituents R13
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are
  • each cyclic alkene is independently a structure contaimng 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • heterocyclic alkene means a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (2) are set forth in Table 2 below. Table 2: Representative Compounds in Formula (2):
  • the compounds are described by formula (3): wherein Ri through Rs, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a.
  • Ri through R 4 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-but
  • Rn is hydrogen or CM alkyl
  • -O(CH2)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl
  • m and n are each independently 0, 1, or 2; O 2005 0
  • X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -COCK
  • R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio]
  • a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio
  • each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-6 alkyl), RwR ⁇ sRi6N + G " (wherein Rw and Ris are each independently hydrogen or Ci-6 alkyl), RwR ⁇ sRi
  • R19 through Rn each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
  • Q represents -CH2CHRnCORi2 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherem R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN-
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl,
  • Rw through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHRuCOR ⁇ 2
  • Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen,
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO- or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each O 2005/041904
  • Rn is hydrogen or CM alkyl
  • -O(CH2)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two s, they together form C3-7 cycloalkyl
  • m and n are each independently 0, 1, or 2
  • X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO- O-,
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi6N + G " (wherein Rw, Ris and Ri6 are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoy
  • R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Ri3,
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9 ⁇ H(wherein R19 represents a hydrogen,
  • each cyclic alkene is independently a structure contaimng 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by ⁇ bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO- or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (3) are set forth in Table 3 below.
  • Ri through R 4 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-e alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci- ⁇ alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, Ci- ⁇ alkyl or benzyl, G represents halogen, SO 4 orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarbox
  • Rn is hydrogen or C alkyl
  • -O(CH2)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • R> and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl
  • m and n is each independently 0, 1 or 2
  • X is -
  • Q represents -CH2CHRnCORi2 ⁇ r -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri through R each independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl,
  • CM alkoxy e.g., n-butoxy, i-butoxy, sec-butoxy
  • RwRisN- wherein Rw and Ris are each independently hydrogen or CM alkyl
  • Rn is hydrogen or CM alkyl
  • -O(CH 2 )kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • R> and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl;
  • m and n is each independently 0, 1 or 2;
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form
  • the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S ⁇ 4 ⁇ rBF4), trifluoromethyl, trifluoromethoxy, halogen, cyan ⁇ , borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl,
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (4) are set forth in Table 4 below. Table 4: Representative Compounds in Formula (4):
  • Ri through Re, m, n, Q, and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl,
  • Rn is hydrogen or CM alkyl
  • -O(CH 2 )kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl
  • m and n is each independently 0, 1 or 2
  • X is
  • R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N- (wherein Rw and R15 are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, Ci- ⁇ alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G ' (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzy
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri tlirough Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxy
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d.
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH.-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (5) are set forth in Table 5 below.
  • Ri through Re, m, n, Q and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S ⁇ 4 ⁇ rBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarbox
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring t may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci- ⁇ alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S ⁇ 4 ⁇ rBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl,
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9 ⁇ H(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (6) are set forth in Table 6 below.
  • Ri through Re, m, n, Q, U, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-buty
  • W is oxygen or lone-pair electrons;
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio]
  • a C5-7 cycloalkane a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio
  • each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), R ⁇ Ri5Ri ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, Ci- ⁇ alkyl or benzyl, G represents halogen, SO 4 orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyan
  • R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each R13 independently represents
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (7) are set forth in Table 7 below.
  • Ri through Re, m, n, Q, U, N, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butyl
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • R19 through R21 each independently represents a hydrogen, Ci- ⁇ alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (8) are set forth in Table 8 below. - Table 8: Representative Compounds in Formula (8):
  • Rt through Rt, 1, m, n, P, Q, V, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRtsRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butyl
  • Rn is hydrogen or CM alkyl
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • 1, m and n is each independently 0, 1 or 2
  • Rn is hydrogen or CM alkyl
  • -O(CH2)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • P and Q each independently represents -CI CHRiiCOR or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, Ci- ⁇ alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, be
  • P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene 'or a heterocyclic alkene, wherein the cycloal
  • RwRi5Ri ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butyls
  • Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents
  • -C(OH) NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kOR ⁇ s- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH- .
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl,
  • R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl.
  • P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, Ci- ⁇ alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (9) are set forth in Table 9 below.
  • Ri tlirough Rt, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S ⁇ 4 ⁇ rBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-but
  • Rn is hydrogen or CM alkyl
  • -O(CH2)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • 1, m and n is each independently 0, 1 or 2
  • Rn is hydrogen or Ci- ⁇ alkyl
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • P and Q each independently represents -CmCHRnCORnor -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, be
  • V represents a nitrogen, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM al
  • Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO- or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl,
  • Ci- ⁇ alkoxy e.g., n-butoxy, i-butoxy, sec-butoxy
  • RwRisN- wherein Rw and Ris are each independently hydrogen or CM alkyl
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri tlirough Rt each independently represents hydrogen, Ct- ⁇ alkyl, C3-7 cycloalkyl, Ci-e alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S torBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy,
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO 2 -, -CO- or -CH2-).
  • L includes -O-, - NH-, -S-, -SO 2 -, -CO- or -CH2-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (10) are set forth in Table 10 below.
  • Ri through R4, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-e alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci- ⁇ alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-but
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • R19 through R21 each independently represents a hydrogen, Ci- ⁇ alkyl, trifluoromethyl or benzyl
  • P and Q each independently represents -CmCHRuCORnor -CHR11COR12
  • Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9 ⁇ H(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Rt through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-but
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • 1, m and n is each independently 0, 1 or 2
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d.
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (11) are set forth in Table 11 below.
  • Ri through R>, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi6 ⁇ + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBEt), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci- ⁇ alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • 1, m, and n is each independently 0, 1, or 2
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
  • P and Q each independently represents -CmCHRuCORi ⁇ or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted
  • CM alkoxy e.g., n-butoxy, i-butoxy, sec-butoxy
  • RwRisN- wherein Rw and Ris are each independently hydrogen or CM alkyl
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl
  • R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl
  • P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C 3 -7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • 1, m, and n is each independently 0, 1, or 2
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, C alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • P and Q each independently represents -CmCHRnCOR ⁇ or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted
  • CM alkoxy e.g., n-butoxy, i-butoxy, sec-butoxy
  • RwRisN- wherein Rw and Ris are each independently hydrogen or CM alkyl
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRtsRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbony
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-.
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (12) are set forth in Table 12 below. Table 12: Representative Compounds in Formula (12):
  • Ri through R2, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci- ⁇ alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-but
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORt9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • 1, m, and n is each independently 0, 1, or 2
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, be
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci- ⁇ alkyl), RwR ⁇ sRi ⁇ N + G ⁇ (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxy
  • Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci- ⁇ alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d.
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (13) are set forth in Table 13 below.
  • Ri through R2, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO 4 orBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-buty
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • Ris is hydrogen or CM alkyl
  • k is 1, 2 or 3
  • -CONR19OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • 1, m, and n is each independently 0, 1, or 2
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Ri and Rz each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S ⁇ 4 ⁇ rBF 4 ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbony
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Ri and Rz each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwR ⁇ sRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, Ci- ⁇ alkyl or benzyl, G represents halogen, SO 4 orBF , trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxy
  • Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d.
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (14) are set forth in Table 14 below.
  • Ri through Re, m, n, Q, U, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological' and other properties required for their use as orally deliverable pharmaceuticals.
  • Ri and R2 each independently represents hydrogen, C alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRi ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S ⁇ 4 ⁇ rBF 4 ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-but
  • Rn is hydrogen or CM alkyl
  • -O(Cm)kOR ⁇ s- wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3
  • -CONR9OH or -CHR2oN(CORi9)OH wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl
  • R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl
  • m and n is each independently 0 or 1
  • X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-
  • R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl);
  • Q represents -CmCHRuCORi ⁇ or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, Ru represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond.
  • One, two or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
  • Rt and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwR ⁇ sRi6N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl,
  • R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio
  • a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio
  • each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5Ri ⁇ N + G " (wherein Rw, Ris and Ri ⁇ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S ⁇ 4 ⁇ rBF4), trifluoromethyl, trifluoromethoxy, halogen
  • R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl
  • Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl
  • R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci- ⁇ alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently
  • each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one • double bond.
  • One, two, or all three rings may be aromatic.
  • One or more carbon(s) may be attached to oxygen to form -CO-.
  • the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-).
  • each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
  • Non-limiting representative compounds of formula (15) are set forth in Table 15 . below.
  • protease has one or more serine or threonine residues at or near the catalytic site.
  • such protease has two or more serine or threonine residues at or near the catalytic site.
  • protease is a cysteine protease, that is , the catalytic residue of the protease is a cysteine.
  • such protease is a 3CL pro .
  • Coronaviruses The boronic acid-based compounds of the present invention can be used to treat infections caused by various viruses and can be used to inhibit protease(s) of various viruses. These various viruses are described in, for example, Fields Nirology (4 th Edition, Lippincott Williams & Wilkins (2001)).
  • the virus belongs to the Coronavindae family.
  • the Coronavindae family includes two genera, coronavirus and torovirus, which share many features of genome organization and replication strategy but have different virion morphology and genome lengths.
  • the viral envelopes are studded with long, petal shaped spikes, giving coronaviruses the appearance of a crown (Latin, corona), and the nucleocapsids are long, flexible helices.
  • Coronavindae characteristics that define Coronavindae include the 3'-coterminal, nested-set structure of the mRNAs, unique RNA transcription strategy, genome organization, nucleotide sequence homology, and the properties of their structural proteins.
  • the virus is a coronavirus.
  • Cornoaviruses a genus in the family Coronaviradae, are large, enveloped, positive-stranded RNA viruses that cause highly prevalent diseases in humans and domestic animals. They have the largest genomes of all RNA viruses and replicate by a unique mechanism, which results in a high frequency of recombination. Virions mature by budding at intracellular membranes, and infection with some coronaviruses induces cell fusion.
  • Coronaviruses were first recognized as a distinct virus group by their characteristic virion morphology in negatively stained preparations. Most coronaviruses can be divided into three serologically distinct groups, although SARS-associated virus does not fit into any of these three known groups. Within each serogroup, the viruses are classified according to their natural hosts, nucleotide sequences, and serologic relationships. Most coronaviruses naturally infect only one animal species or, at most, a limited number of closely related species. Virus replication in vivo can be either disseminated, causing systemic infections, or restricted to a few cell types, often the epithelial cells of the respiratory or enteric tracts and macrophages, causing localized infections.
  • Group I coronaviruses include, for example, HCoV-229E (human respiratory coronavirus), TGEV (porcine transmissible gatroenteritis virus), PRCoN (porcine respiratory coronavirus), CCoN (canine coronavirus), FECoN (Feline enteric coronavirus), FIPN (feline infectious peritonitis virus), and RbCoN (rabbit coronavirus).
  • Group II coronaviruses include, for example, HCoN-OC43 (human respiratory coronavirus), MHV (murine hepatitis virus), SDAN (sialodacryoadenitis virus), HEV (porcine hemagglutinating encephalomyelitis virus), and BCoV (bovine coronavirus).
  • Group III coronaviruses include, for example, IBV (avain infectious bronchitis virus) and TCoV (turkey coronavirus). The SARS-associated coronavirus genome appears to be closer to the murine, bovine, porcine, and human coronaviruses in Group I ⁇ and avian coronavirus IBV in Group I.
  • Non-limiting examples of the coronavirus include SARS-associated virus, rat coronavirus (ATCC Nos. VR-1410 (Sialodacryoadenitis virus, deposited as rat coronavirus), and VR-882), murine hepatitis virus (ATCC Nos. VR-1426, VR-246, VR- 261, VR-764, VR-765 (murine hepatitis virus deposited as mouse hepatitis virus), and VR- 766), human enteric coronavirus (ATCC No. VR-1475), feline coronavirus (ATCC Nos. VR-2004, VR-2009.
  • SARS-associated virus ATCC Nos. VR-1410 (Sialodacryoadenitis virus, deposited as rat coronavirus), and VR-882)
  • murine hepatitis virus ATCC Nos. VR-1426, VR-246, VR- 261, VR-764, VR-765 (murine hepatitis virus deposited as mouse hepatitis
  • VR-2125, VR-2126, VR-2127, VR-2128, VR-2201, VR-2202, VR- 867, VR-989, and VR-990 canine coronavirus
  • canine coronavirus ATCC Nos. VR-2068 and VR-809
  • infectious bronchitis virus ATCC Nos. VR-21, VR-22, VR-817, and VR-841
  • human coronavirus 229E ATCC No. VR-740
  • transmissible gastroenteritis virus prorcine respiratory coronavirus
  • human coronavirus OC43 ATCC No. VR-759
  • bovine coronavirus calf diarrheal coronavirus
  • VR- 874 rat coronavirus
  • ATCC No., VR-882 turkey coronavirus
  • ATCC No. VR-911 turkey coronavirus
  • rabbit coronavirus ATCC No. VR-920
  • transmissible gastroenteritis virus ATCC No. VR-2384.
  • Salts and Derivatives Various pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility- altering derivatives of the active compound also are encompassed by the present invention.
  • the present invention further includes all individual enantiomers, diastereomers, racemates, and other isomer of the compound.
  • the invention also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of this compound. Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution, based on the disclosure provided herein.
  • Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyravic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic or in
  • Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-memylglucamine ammonium salt, o
  • a prodrug is a pharmacologically inactive compound that is converted into a pharmacologically active agent by a metabolic transformation. In vivo, a prodrug is acted on by naturally occurring enzyme(s) resulting in liberation of the pharmacologically active agent. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • An active metabolite is a compound which results from metabolism of another compound after administration of the latter to a subject. Metabolites can be identified by techniques well-known in the art.
  • Suitable dosage forms include but are not limited to oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra- uterille administration, and other dosage forms for systemic delivery of active ingredients.
  • the dosage form is suitable for injection.
  • To prepare such pharmaceutical dosage forms one or more of the aforementioned compounds of formulae (A), (B) and (1)-(15), are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of fo ⁇ ns depending on the form of preparation desired for administration.
  • the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed. ' In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like.
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
  • a suitable biomolecule such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
  • Treatment methods of the present invention using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules.
  • a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
  • a tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent.
  • Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
  • a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s).
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
  • Formulations suitable for parenteral administration usually comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution).
  • inhalable forms can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents.
  • Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier.
  • Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
  • Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
  • Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
  • a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose
  • formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
  • the formulation of the present invention can have immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.
  • the subject is preferably an animal, including, but not limited, to an animal such a cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, etc., and is more preferably a mammal, and most preferably a human.
  • step (i) of general procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of carboxyl boronic acid derivative A-1 (0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride A-2 as a yellow solid, which was used without further purification.
  • step (ii) a solution of the acid chloride A-2 (0.2 mmol, obtained from step (i) above) in 5 mL of anhydrous CH2CI2 was added dropwise to an ice-cold solution of A-3, anhydrous triethyl amine (42 ⁇ L, 0.3 mmol) and 10 mL of anhydrous CH2CI2.
  • the reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was then dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHC03,.. saturated brine solution, dried (Na2SO 4 ) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10).
  • the product yielded from step (ii) is A-4.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ⁇ -nitrophenol (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 36 mg (72% yield) of the desired compound as a pale yellow powder, mp: 128-130°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2O2. The reaction was stirred overnight at room temperature and then evaporated to dryness.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with -methoxyphenol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (81% yield) of the desired compound as a white needle, mp: 67°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ethyl 4-hydroxybenzoate (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 51 mg (94% yield) of the desired compound as a white powder, mp: 230-232°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 6-hydroxy-l,3-benzoxathiol- 2-one (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 50 mg (92% yield) of the desired compound as a white powder, mp: 145-147°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-hydroxybenzonitrile (18 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (92% yield) of the desired compound as a white powder, mp: 248-250°C. 1 H-NMR(400MHz, 5%D 2 O in d 6 -
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-6-nitrophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (71% yield) of the desired compound as a yellow needle, mp: 179°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ethyl salicylate (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (64% yield) of the desired compound as a yellow semisolid.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with o-chlorophenol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 44 mg (90% yield) of the desired compound as a white powder, mp: 138-140°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ⁇ -cresol (16 mg, 0.15 mmol) 15 according to general procedure A, step (ii), to give 40 mg (89% yield) of the desired compound as a yellow powder, mp: 175°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then5 evaporated to dryness. The product obtained was reacted with guaiacol (19 mg, 0.15 mmol) O 2005/041904
  • step (ii) to give 44 mg (92% yield) of the desired ccoommppoouunndd aass aa yyeellllooww sseemmiissoolliidd..
  • II H ⁇ --NNMMRR((330000MMH ⁇ zz,, 55%%DD :2 O in d 6 -OMSO): J3.69[s, 3H, OCHjJ, 7.46-8.03 [m, 4 ⁇ , Ar-HJ, 8.64-8.97 [m, 3 ⁇ , Ar-HJ.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous ' CH2C ⁇ 2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with m-cresol (16 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (82% yield) of the desired compound To make compound (lm), was treated according to general procedure A, step (ii), to give 41 mg (91% yield) of the desired compound as a yellow semisolid.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-dichlorophenol (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (80% yield) of the desired compound as a pale yellow powder, mp: 167-169°C. 1 H-NMR(300MHz, 5%D 2 O in O 2005/041904
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous C ⁇ 2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-fluoropl ⁇ enol (17 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (85% yield) of the desired compound as a white needle, mp: 144-146°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous C ⁇ 2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-difluoro ⁇ henol (20 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (81% yield) of the desired compound as a white powder, mp: 124-126°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-fluoro ⁇ henol (17 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (89% yield) of the desired compound as a white powder, mp: 233-235°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4- ⁇ yridinol (14 mg, 0.15 mmol) according to general procedure A, step (ii), to give 34 mg (79% yield) of the desired compound as a pale yellow powder, mp: 165°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-3- ⁇ yridinol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 37 mg (77% yield) of the desired compound as a white powder, mp: 146-148°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-bromo-l-indanol (32 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (71% yield) of the desired compound as a white powder, mp: 177-179°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous C ⁇ 2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with phenol (14 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (91% yield) of the desired compound as a white needle, mp: 139-141°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ l, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous C ⁇ 2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-nitrobenzyl alcohol (23 mg, O 2005/041904
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophe ⁇ yl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-chlorobenzyl alcohol (22 mg, 0.15 mmol) according to general procedure A, step (ii), to give 44 mg (88% yield) of the desired compound as a white powder, mp: 91°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-bromophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 49 mg (90% yield) of the desired compound as a pale yellow powder, mp: 128-130°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with benzoin (32 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (71% yield) of the desired compound as a white powder, mp: 237°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 32 mg (64% yield) of the desired compound as a pale yellow powder, mp: 228-230°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of ,(3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3- hydroxymethylphenylboronic acid (23 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (68% yield) of the desired compound as a yellow semisolid.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous C ⁇ 2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-6-nitrophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 40 mg (79% yield) of the desired compound as a pale yellow powder, mp: 174-175°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,4-dichloro-6-nitrophenol (80%) (39 mg, 0.15 mmol) according to general procedure A, step (ii), to give 52 mg (87% yield) of the desired compound as a pale yellow powder, mp: 184-186°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 5-chloro-2-(2,4- dichloro ⁇ henoxy) ⁇ henol (43 mg, 0.15 mmol) according to general procedure A, step (ii), to give 51 mg (71% yield) of the desired compound as a pale yellow powder, mp: 193°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-hydroxy coumarin (24 mg, 0.15 mmol) according to general procedure A, step (ii), to give 36 mg (67% yield) of the desired compound as a white powder, mp: 230-232°C.
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,4,6-trichlorophenol (30 mg, 0.15 mmol) according to general procedure A, step (ii), to give 45 mg (77% yield) of the desired compound as a white powder, mp: 217°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1-naphthalenemethanol (24 mg, 0.15 mmol) according to general procedure A, step (ii), to give 38 mg (73% yield) of the desired compound as a pale yellow powder, mp: 230°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous C ⁇ 2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with (40 mg, 0.15 mmol) according to general procedure A, step (ii), to give 40 mg (70% yield) of the desired compound as a pale yellow powder, mp: 217°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of, DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-naphthol (22 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (82% yield) of the desired compound as a pale yellow powder, mp: 256°C(dec).
  • step (i) of procedure A oxalyl chloride (35 ⁇ l, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Q2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3- hydroxymethylphenylboronic acid (23 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (68% yield) of the desired compound as a yellow semisolid.
  • step (i) oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of compound B-l (0.2 mmol), 1 drop of DMF and 5 mL of dried CH2CI2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride B-2 as a solid, which was used without further purification in step (ii).
  • step (ii) a suspension of the acid chloride B-2 (0.2 mmol, obtained from step (i) above) in 5 mL of dried THF was added dropwise to an ice-cold solution of B-3 (0.075 mmol), anhydrous triethyl amine (42 ⁇ L, 0.3 mmol) and 10 mL of anhydrous THF.
  • the reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10).
  • the product yielded from step (ii) is B-4.
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with hydroquinone (9 mg, 0.075 mmol) according to general procedure B, step (ii), to give 32 mg (86% yield) of the desired compound as a white powder, mp: 271-273°C.
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with chlorohydroquinone (11 mg, 0.075 mmol) according to general procedure B, step (ii), to give 31 mg (78% yield) of the desired compound as a white powder, mp: 264-266°C.
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with and chlorohydroquinone (11 mg, 0.075 mmol) according to general procedure B, step (ii), to give 26 mg (74% yield) of the desired compound as a pale yellow powder, mp: 228-230°C.
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with resorcinol (9 mg, 0.075 mmol) according to general procedure B, step (ii), to give 26 mg (70% yield) of the desired compound as a pale yellow powder, mp: 134°C(dec).
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1,2-benzenedimethanol (10 mg, 0.075 mmol) according to general procedure B, step (ii), to give 21 mg (53% yield) of the desired compound as a pale yellow powder, mp: 142°C(dec).
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted tetrachlorohydroquinone (19 mg, 0.075 mmol) according to general procedure B, step (ii), to give 33 mg (69% yield) of the desired compound as a white powder, mp: 252°C.
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1,4-naphthalenediol (12 mg, 0.075 mmol) according to general procedure B, step (ii), to give 24 mg (59% yield) of the desired compound as a pale yellow powder, mp: 270°C(dec).
  • step (i) of procedure B oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with tert-butylhydroquinone (12 mg, 0.075 mmol) according to general procedure B, step (ii), to give 22 mg (43 % yield) of the desired compound as a brown powder, mp: 268°C(dec).
  • step (i) oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of compound E-1 (0.2 mmol), 1 drop of DMF and 5 mL of dried CH2CI2. The reaction mixture was sti ⁇ ed at room temperature overnight and then evaporated to dryness to afford acid chloride E-2 as a solid, which was used without further purification in step (ii).
  • step (ii) a suspension of the acid chloride E-2 (0.2 mmol, obtained from step (i) above) in 5 mL of dried THF was added dropwise to an ice-cold solution of E-3 (0.075 mmol), anhydrous triethylamine (42 ⁇ L, 0.3 mmol) and 10 mL of anhydrous THF.
  • the reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ether and washed with IN aqueous HCI, 10% aqueous NaHCO 3 , saturated brine solution, dried (Na2SO 4 ) and then concentrated. The residue was recrystallized from ethyl acetate/hexane.
  • the product yielded from step (ii) is E-4.
  • step (i) of procedure E oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with J-phenylenediamine (8 mg, 0.075 mmol) according to general procedure E, step (ii), to give 29 mg (78% yield) of the desired compound as pale yellow powder, mp: 254-256°C.
  • step (i) oxalyl chloride (79 ⁇ L, 0.9 mmol) was added to a suspension of (3 ⁇ carboxyl-5- nitrophenyl)boronic acid (95 mg, 0.45 mmol), 1 drop of DMF and 10 mL of dried CH 2 C1 2 . The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).
  • step (ii) a suspension of the above acid chloride (0.45 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of phloroglucinol (13 mg, 0.1 mmol), anhydrous triethylamine (63 ⁇ L, 0.45 mmol) and 10 mL of anhydrous THF.
  • the reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO 3 , saturated brine solution, dried (Na 2 SO 4 ) and then concentrated.
  • step (i) oxalyl chloride (79 ⁇ L, 0.9 mmol) was added to a suspension of (3-carboxyl-5- nitrophenyl)boronic acid (95 mg, 0.45 mmol), 1 drop of DMF and 10 mL of dried CH 2 C1 2 . The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).
  • step (i) oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5- nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 10 mL of dried CH 2 C1 2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).
  • step (ii) a solution of the above acid chloride (0.2 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of L-phenylalanine ethyl ester hydrochloride (34 mg, 0.15 mmol), anhydrous triethylamine (63 ⁇ L, 0.45 mmol) and 10 mL of anhydrous THF.
  • the reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO 3 , saturated brine solution, dried (Na 2 SO ) and then concentrated.
  • 3-amino-5-carboxylphenylboronic acid hydrochloride (22 mg, 0.1 mmol) was suspended in 2 mL of 50% H 2 SO 4 and treated at -5 °C with a solution of NaNO2 (8 mg, 0.1 mmol) in 1 mL of water. After the mixture had been stirred for 1 h at this temperature, water (10 mL) was added and the mixture was warmed to 60 °C until the evolution of gas ceased. The dark brown solution was extracted twice with ether, and the extracts were washed with water and brine and dried with Na 2 SO .
  • FL-1201 is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2188).
  • FL-1010 is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-3055).
  • EXAMPLE 2 Cloning of Recombinant SARS-Associated 3CL pro Protease cDNA corresponding to the SARS 3CL protease gene (Tor2 strain, GenBank #AY274119) inserted in a pBR194c vector was kindly provided by British Columbia Cancer Agency Branch (Vancouver, British Columbia, Canada). Competent cells (XL-1 Blue, Stratagene) were transformed for plasmid propagation under ampicillin selection.
  • DNA plasmid was isolated (Plasmid Midi Kit, Qiagen) and the gene was amplified by PCR with appropriate primers using Pfu Turbo DNA Polymerase (Stratagene). To prevent artifacts afterward, the original plasmid was degraded by Dpnl (Stratagene) digestion reaction (1 hour at 37°C) followed by inactivation of Dpnl (20 minutes at 80°C). Cloning reaction was performed by blunt-end directional cloning (Champion pET Directional TOPO Expression and Cloning Kit, Invitrogen) by topo-isomerase reaction in a pETlOO vector, where the protein expression is chemically induced and under the control of the T7 promoter.
  • protease gene was cloned in frame with an N-terminal peptide containing a poly-histidine tag for further purification by affinity chromatography. An enterokinase recognition site was present to remove the amino terminal tag after purification.
  • One Shot TOP 10 competent cells (Invitrogen) were transformed with the product from the cloning reaction. DNA plasmid was purified and the gene insertion and its directionality, as well as the integrity of pETlOO vector were confirmed by DNA sequencing.
  • BL21 Star DE3 (Invitrogen) competent cells were transformed for protein expression under ampicillin selection and IPTG induction.
  • the supernatant was diluted 1:3 with binding buffer (sodium phosphate 50 mM, pH 7.5, sodium chloride 0.3 M, imidazole 10 mM), filtered using a 0.22 m pore size filter (Millipore) and applied directly to a nickel-affinity column (HisSelect, Sigma) which had been pre-equilibrated with five column volumes of the binding buffer.
  • the protease was eluted with a linear gradient of elution buffer (sodium phosphate 50 mM, pH 7.5, sodium chloride 0.3 M, imidazole 250 mM) at fractions corresponding to 0 - 30% elution buffer. Protease fractions were pooled and concentrated.
  • the elution buffer was exchanged gradually for storage buffer (sodium phosphate 10 mM, pH 7.4, sodium chloride 10 mM, DTT 1 mM, EDTA 0.5 mM).
  • the poly-histidine tag of the fusion protein was cut through incubation with 0.1 units of enterokinase (Invitrogen) for 48 hours at 4°C. Efficiency of the cleavage reaction was inspected by SDS PAGE. This reaction mixture was passed again through the nickel-affinity column and the flow-through containing the protease was collected. The sample was diluted 4-fold with storage buffer and then concentrated (> 10 mg/ml). The purified protein was then stored at -20°C. Purity of the sample was higher than 95% , assessed by SDS PAGE.
  • EXAMPLE 4 Enzymatic Characterization of Recombinant SARS-Associated 3CL pro Protease
  • the activity of the SARS protease was determined by continuous kinetic assays using the fluorogenic substrate Dabcyl-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Arg-Edans (Bachem).
  • the hydrolysis of the substrate is accompanied by a proportional increase of the fluorescence intensity of the Edans group due to a decreased FRET efficiency following the release of the Dabcyl-linked peptide quencher fragment.
  • the fluorescent intensity was monitored in a Cary Eclipse fluorescence spectrophotometer (Varian) using wavelengths of 360 nm and 500 nm for the excitation and emission, respectively.
  • Inhibition assays were performed under the same conditions at increasing concentration of inhibitor.
  • Protease final concentration 1 ⁇ M
  • the inhibitor final concentration 0 - 150 ⁇ M
  • the reaction was initiated adding substrate to a final concentration of 5 ⁇ M.
  • Inhibition constants, i were obtained as adjustable parameters through non-linear square fitting of the initial enzymatic rates as a function of the inhibitor concentration according to the following equation: v, _ t [I] ⁇ +[E] T +K ⁇ - ([IJ T +[E] T +K t . -4[I] T [EJ T v 0 2[EJ T
  • SARS-associated coronavirus protease 3CL pro inhibitors described in this disclosure Table 16. Inhibition of SARS Associated Coronavirus Protease 3CL pro by Boronic Acids

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Abstract

This invention provides organic boron-containing compounds, compositions thereof, and methods of using such compounds and compositions for inhibiting coronavirus protease(s) and for treating infections.

Description

INHIBITORS OF CORONAVTRUS PROTEASE AND
METHODS OF USE THEREOF STATEMENT OF GOVERNMENT INTEREST
A portion of this invention was made with support under Grant No. GM-57144, awarded by the National Institutes of Health. The United States Government may have certain rights in this invention.
CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority under 35 U.S.C. § 119(e) of provisional application 60/516,008, filed October 31, 2003, which is hereby incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to boron-containing compounds that are inhibitors of coronavirus protease and methods of use thereof. BACKGROUND OF THE INVENTION
Severe Acute Respiratory Syndrome (SARS) The first cases of Severe Acute Respiratory Syndrome (SARS) appeared at the end of 2002 in Southern China. By May 2003, SARS had spread to other continents through international travel. It is estimated by the World Health Organization that a total of 15,000 people were infected during the outbreak with an average mortality rate of 15 % . The actual mortality rate appears to depend on the age of the patient. The fatality ratio is estimated to be less than 1% in persons aged 24 years or younger, 6% in persons aged 25 to 44 years, 15% in persons aged 45 to 64 years, and greater than 50% in persons aged 65 years and older. SARS patients typically have high fever, malaise, rigor, headache and nonproductive cough or dyspnea and may progress to generalized interstitial infiltrated in the lung, requiring incubation and mechanical ventilation. The causative agent of SARs is a coronavirus never before seen in humans. The genome of the SARS-associated coronavirus has been sequenced. The genome sequence of the SARS-associated coronavirus reveals that the virus does not belong to any of the known groups of coronaviruses, including two human coronaviruses, HCoN-OC43 and HCoN-229E (Drosten et al. , Identification of a Novel Coronavirus in Patients with Severe Acute Respiratory Syndrome. N. Engl. J. Med. (2003); 348:1967-1976; Marra et al. , Science (2003); 300:1399-1404; and Rota et al. , Science (2003); 300:1394-1399). The SARS-associated coronavirus genome appears to be closer to the murine, bovine, porcine, and human coronaviruses in Group II and avian coronavirus IBN in Group I (Marra et al.,. Science 300:1399-404 (2003)). At present, no effective therapy is available for the treatment of SARS.
Boron-Containing Compounds Boric acid and various boronic acids have been used as inhibitors of β-lactamases (Koehler et al. , Biochemistry 10 , 2477- 2483 (1971); Kiener et al. , Biochem. J. , 169, 197-204 (1978) (boric acid, phenylboronic acid and m-aminophenylboronate); Beesley et al., Biochem. J. , 209, 229-233 (1983) (twelve substituted phenylborinic acids, including 2-formylphenylboronate, 4-formylphenylboronate, and 4-methylphenylboronate; and Amicosante et al., J. Chemotherapy, 1, 394-398 (1989) (boric acid, phenylboronic acid, m-aminophenylboronate and tetraphenylboronic acid)). m-(Dansylamidophenyl)- boronic acid has also been reported to be a submicromolar inhibitor of the Enterobacter cloacae P99 β-lactamase (Dryjanski et al , Biochemistiy, 34, 3561-3568 (1995)). In addition, Strynadka and colleagues used the crystallographic structure of a mutant TEM- 1 enzyme-penicillin G complex to design a novel alkylboronic acid inhibitor [(1R)-1- acetamido-2-(3-carboxyphenyl)ethane boronic acid] with high affinity for this enzyme. (Strynadka et al, Nat. Struc. Biol. , 3, 688-695 (1996)). Various other boronic-acids are known and used as β-lactamase inhibitors, (e.g. , Tondi et al., Chemistry & Biology, 8, 593-610 (2001); Martin et al., Bioorganic & Medicinal Chemistry Letters, 4(10), 1229- 1234 (1994); Weston et al., J. Med. Chem. , 41, 4577-4586 (1998); U.S. Patents No. 6,075,014 and 6,184,363; and U.S. Provisional Patent Application Serial No. 60/477,636, filed June 10, 2003, and co-pending U.S. patent application serial no. 10/866,179, filed June 10, 2004, both entitled "Beta-Lactamase Inhibitors and Methods of Use Thereof". No boron-containing compounds have been reported as inhibitors of coronavirus protease inhibitors.
Citation or identification of any references in the "Background of the Invention" or anywhere in the specification of this application is not an admission that such references available as prior art to the present invention.
SUMMARY OF THE INVENTION The present invention relates to boron-containing compounds. In one particular embodiment, such compounds are boric acid and boronic acids. In another particular embodiment, such compounds are organic boron-containing compounds. In a first preferred embodiment, the compounds are described by formula (1):
In a second preferred embodiment, the compounds are described by formula (2):
In a third preferred embodiment, the compounds are described by formula (3):
In a fourth preferred embodiment, the compounds are described by formula (4):
In a fifth preferred embodiment, the compounds are described by formula (5):
In a sixth preferred embodiment, the compounds are described by formula (6):
In a seventh preferred embodiment, the compounds are described by formula (7):
In an eighth preferred embodiment, the compounds are described by formula (8):
In a ninth preferred embodiment, the compounds are described by formula (9):
In a tenth preferred embodiment, the compounds are described by formula (10):
In an eleventh preferred embodiment, the compounds are described by formula (11):
In a twelfth preferred embodiment, the compounds are described by formula
(12):
In a thirteenth preferred embodiment, the compounds are described by formula (13):
In a fourteenth preferred embodiment, the compounds are described by formula
(14):
In a fifteenth preferred embodiment, the compounds are described by formula
(15):
Ri through Rs, 1, m, n, P, Q, U, N, W, X, Y, and Z in formulae (1)-(15) can vary as set forth below, in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. The invention also provides a method of inhibiting coronavirus protease(s), particularly coronavirus protease(s) that has one or more serine or threonine residue(s) at or near its active site, more particularly protease of SARS-associated coronavirus. The method comprises contacting the protease(s) with an effective amount of one or more boron-containing compounds, particularly compounds of formulae (1)-(15). The invention additionally provides a method of treating infections caused by coronavirus, particularly by coronavirus that has protease(s) with one or more serine or threonine residue(s) at or near the protease active site, more particularly by SARS- associated coronavirus. Such method comprises administering to a subject suffering from such infections an effective amount of one or more boron-containing compounds, particularly compounds of formulae (1)-(15). The invention further provides a method of detecting coronavirus, particularly coronavirus that has protease(s) with one or more serine or threonine residue(s) at or near the protease active site, more particularly by SARS-associated coronavirus. Such method comprises contacting the testing sample obtained from a patient with boron- containing compounds of formulae (1)-(15) that have been (1) tethered to an appropriate surface such that protease that becomes in contact and bound to the tethered compound can be detected; (2) labeled by fluorescent, radioactive or other markers that allow identification of coronavirus protease bound to the compound; or (3) that by any other mean can be used to detect the presence of coronavirus protease. The invention also provides a pharmaceutical composition comprising one or more boron-containing compounds, particularly compounds of formulae (1)-(15), and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1. shows a sequence alignment of identified SARS-associated coronavirus protease and the MHV protease. Identities are shown in dark grey and similarities in light grey. Fig. 2. shows an alignment of sequences around the serine cluster for sequences identified by BLAST search with SARS-associated coronavirus protease 3CLpro.
DETAILED DESCRIPTION
Analysis of the SARS-associated coronavirus genome identified the coding region for an essential protease (3CLpr0) homologous to that of other coronaviruses. The 3CLpro coding is shown in Fig. 1 and in SEQ ID NO: 1. The highest homology was found with the mouse hepatitis coronavirus picorna 3C-like endopeptidase [MER02029 ] (MHN Protease) [SEQ ID NO: 2]. The alignment of the two sequences is shown in Fig. 1. The sequences of the two enzymes are 50% identical (dark grey in Fig. 1) and ' 72% similar (dark grey and light grey in Fig. 1). These proteases are characterized by a catalytic cysteine (Cys 145) and histidine (His 41) and therefore are classified as cysteine proteases since the nucleophilic catalytic residue is a cysteine. These cysteine proteases are essential to the viral reproductive cycle since they are involved in the processing of all downstream domains of the replicase polyproteins of these viruses (Ziebuhr et al. , (2000). Virus-encoded proteinases and proteolytic processing in the Nidovirales. J. Gen. Virol. 81, 853-879). For this reason, inhibition of this enzyme has been shown to inhibit viral replication in mouse hepatitis virus (MHV) infected cells (Kim et al., (1995). Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology 208, 1-8). The cleavage sites for the 3C-like viral proteases that have been studied are highly conserved, the PI site being exclusively occupied by Gin and the PI' site by small aliphatic residues (Ser, Ala, Asn, Gly, Cys). The crystallographic structure of the SARS-associated coronavirus CL3pro protease is available in the public protein database (accession code lq2w). Analysis of the active site of the protease reveals a cluster of serines (Ser 139, Ser 144 and Ser 147). The serine cluster in the SARS-associated coronavirus protease 3CLpro is highly conserved in similar proteins from other coronavirus indicating that either the same compound or similar compounds can be used to target this region of the binding site and inhibit these proteases. In addition, the entire region is highly conserved opening the possibility for wide spectrum antivirals targeting this region of the protease. Fig. 2 shows the sequence alignments between residues 121 and 160 for the proteases of twenty different coronaviruses. Conserved serine residues being targeted are boxed. The sequences shown are from the following Genbank accession numbers for protein sequences: SARS-HCN (severe acute respiratory syndrome-human coronavirus): ΝP_828863 [SEQ ID NO: 3]; MHV ML-10 (murine hepatitis virus strain ML-10):
AAF69341 [SEQ ID NO: 4]; MHV A59 (murine hepatitis virus strain A59): NP_740610 [SEQ ID NO: 5]; MHV JHM (murine hepatitis virus strain JHM): P19751 [SEQ ID NO: 6]; MHV-2 (murine hepatitis virus strain 2): AAF19383 [SEQ ID NO: 7]; MHV Penn 97-1 (murine hepatitis virus strain Penn 97-1): AAF69331 [SEQ ID NO: 8]; MHV ML- 11 (murine hepatitis virus strain ML-11): AAF68919 [SEQ ID NO: 9]; BCV Quebec (bovine coronavirus strain Quebec): AAL40396 [SEQ ID NO: 10]; BCV LUN (bovine coronavirus strain LUN): AAL57315 [SEQ ID NO: 11]; BCV Mebus (bovine coronavirus strain Mebus): AAA64744 [SEQ ID NO: 12]; BCV ENT (bovine coronavirus strain ENT): NP_742132 [SEQ ID NO: 13]; PEDV-CV777 (porcine epidemic diarrhea virus strain CV777): NP_839959 [SEQ ID NO: 14]; TGEV Purdue- 115 (transmissible gastroenteritis virus strain Purdue- 115): CAA83979 [SEQ ID NO: 15]; TGEV PUR46-MAD (transmissible gastroenteritis virus strain PUR46-MAD): NP_840003 [SEQ ID NO: 16]; FIPV 79-1146 (feline infectious peritonitis virus strain 79-1146): AAK09095 [SEQ ID NO: 17]; HCV 229E (human coronavirus strain 229E): NP_835346 [SEQ ID NO: 18]; IBV Beaudette (avian infectious bronchitis virus strain Beaudette): NP_740623 [SEQ ID NO: 19]; IBV LX4 (avian infectious bronchitis virus strain LX4): AAQ21584 [SEQ ID NO: 20]; IBN Beaudette CK (avian infectious bronchitis virus strain Beaudette CK): CAC39112 [SEQ ID NO: 21]; IBV BJ (avian infectious bronchitis virus strain BJ): AAP92674 [SEQ ID NO: 22]. Without being bound by any particular theory, serine or threonine, particularly serine cluster, threonine cluster, and serine/threonine cluster, are chosen as a prime target site because the OH groups in serine and threonine residues are highly reactive with boron-containing compounds, particularly boric acid and boronic acids. Moreover, without being bound by any particular theory, since the coronavirus proteases such as SARS-associated coronavirus protease 3CLpro contains a cluster of two or more serines and/or threonines (SARS-associated coronavirus protease contains a cluster of three serines), it is believed that multifunctional boron-containing compounds (i.e., a compound containing two or more boron atoms), particularly multifunctional boronic acids (i.e., a compound containing two or more
-B(OH)2 groups) would be even more potent, selective, and hence more effective than the monofunctional boron-containing compounds (i.e., a compound containing only one boron atom). The boron-containing compounds of the present invention can be organic compounds that contain boron. Non-limiting examples of such boron-containing compounds include arylboronic acid, arylborates, arylboranes, alkylboronic acids, alkyl borates, alkylboranes and boron heterocyclics, and boron-containing compounds disclosed in Koehler et ah, Biochemistry 10, 2477- 2483 (1971); Kiener et al., Biochem. J. , 169, 197-204 (1978); Beesley et al. , Biochem. J. , 209, 229-233 (1983); Amicosante et al., J. Chemotherapy, 1, 394-398 (1989); Dryjanski et al. , Biochemistry, 34, 3561-3568 (1995); Strynadka et al., Nat. Struc. Biol. , 3, 688-695 (1996); Tondi et al., Chemistry & Biology, 8, 593-610 (2001); Martin et al., Bioorganic & Medicinal Chemistry Letters, 4(10), 1229-1234 (1994); Weston et al., J. Med. Chem. , 41, 4577- 4586 (1998); U.S. Patents 6,075,014 and 6,184,363; and co-pending U.S. Provisional Patent Application Serial No. 60/477,636, entitled "Beta-Lactamase Inhibitors and Methods of Use Thereof," filed: June 10, 2003. In one particular embodiment, the compound of the present invention is a compound described by formula (A) HO B OH (A) T wherein Tt comprises a ring structure or any other organic functional group; and B is boron. Non-limiting examples of Ti include cycloalkyl, cyclic alkene or heterocyclic alkene with one or more substituents R. In another particular embodiment, the compound of the present invention is a compound described by formula (B)
wherein Ti and T3 each comprises a ring structure or any other organic functional group; and T2 is a linker; and B is boron. Non-limiting examples of Ti and T3 include cycloalkyl, cyclic alkene or heterocyclic alkene with one or more substituents R. Non-limiting examples of the linker T2 include di-branched linker such as -(CH2 -, -(CH=CH)j-, -(CH2CH2O)j- or -(CEbC N))- (wherein i = 0, 1, 2, 3,
4, 5, or 6, and j = 0, 1, or 2), -CHR-, any di-branched cycloalkane, cyclic alkene or heterocyclic alkene with one or more substituents R, -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, - NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N- etc; each R independently represents any group, non-limiting examples include hydrogen, O- 6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, t'-butoxy, sec-butoxy) trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, carboxyl, Cι-6 alkylcarboxyl, Ci-e alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C1-6 alkylcarbonyl C1-6 alkylcarbonyl, -CH=NOH, - ClfeNHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3 and -SO2CH3 etc. Non-limiting examples of cyclic alkene include, benzene, naphthalene, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, indene, fluorene, anthracene and phenanthrene. Non-limiting examples of heterocyclic alkene include, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, triazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, benzofuran, thionaphtene, indole, dibenzofuran, dibenzothiophene, carbazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, coumarin, quinoline, isoquinoline, acridine, phenothiazine and phenazine. In another particular embodiment, the compound of the present invention is a multifunctional boron-containing compound (i.e., a compound containing two or more boron atoms). In another particular embodiment, the compound of the present invention is a multifunctional boronic acid (i.e., a compound containing two or more -B(OH)2 groups). This application includes Tables 1-15 which set forth without limitation representative compounds 1-403. In all cases, when a compound no. is listed in more than row of tables 1-15, it is to be understood that all of the substituents listed for a given compound no. are found together on a single compound. In Table 1, for example, compound no. 1 comprises the groups Rι=H, R2=H, R3—NO2, Rt=H, R7=H, Rs=H,
-X- = -CO-O-, -Y- = -O-CO-, m=0, n=0, and U= . All other compounds listed in Tables 1-15 are to be similarly construed.
1. First Preferred Embodiment In a first preferred embodiment, the compounds are described by formula (1):
wherein Ri through Rs, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 1-a In a more preferred first embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, C alkoxy (e.g., n-butoxy, z-butoxy, .sec-butoxy), RwRisN- (wherein Rι4 and R15 are each independently hydrogen or C1-6 alkyl), Rι4Ri5RiδN+G~ (wherein Rw, R15 and Ri6 are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-e alkyl), -O(CH2>ORι8- (wherein Ris is hydrogen or Ci-β alkyl, and k is 1, 2 or 3), -CONR19OH or
CHR2oN(CORi9)OH( wherein R19 and R20 each independently represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> through Rs each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, - CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH2)i-, -(CH=CH)j-, -(CaCrfcO)]- or -(CH2CH2N)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents C1-6 alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RπRisN- (wherein Rw and R15 are each independently hydrogen or C1-6 alkyl), Ri4Ri5RιeN+G" (wherein Rι , R15 and Ri6 are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, Ct-e alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CMS alkyl), - O(CH2)jORι8- (wherein Ris is hydrogen or Ci-β alkyl, and j is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -QE CHRπCORuor -CHRnCORι2 [wherein Rn represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), - NRi9OH(wherein R19 represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RuRisN- (wherein Rw and R15 are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N- (wherein Rι4 and R15 are each independently hydrogen or C1-6 alkyl), Rι4Ri5Ri6N+G" (wherein R14, R15 and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t- butylsilyloxy, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or G-e alkyl), -O(CH2)kORi8- (wherein Ris is hydrogen or Ci-e alkyl, and k is 1, 2 or 3), -CONR19OH or
-CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen,
Ci-e alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 1-b In another more preferred embodiment of the first embodiment, Ri through Rt each independently represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, Ci-β alkoxy, RwRisN- (wherein Rι4 and R15 are each independently hydrogen, C1-6 alkyl or benzyl), Ri4RisRi6N+G" (wherein Rι4, R15 and Riβ are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3,
-SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl); Rs through Rs each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0 or 1; X and Y are each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH2)i or -(CH=CH)j(wherein i = 0, 1, 2, 3 or 4 and j = 0 or 1),
-CHR9- [wherein R> represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, C1-6 alkyl, R14R15N- (wherein Rι4 and R15 are each independently hydrogen or Ci-β alkyl), Rι4RιsRi6N+G" (wherein Rw, R15 and Ri6 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ct-β alkylcarboxyl, O-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, Ci-e alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3,
-SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, Cw alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), - NRi9OH(wherein R19 represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N- (wherein Rι4 and R15 are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C1-6 alkyl, R14R15N- (wherein Rι4 and R15 are each independently hydrogen or Ci-β alkyl), Rι4Ri5Ri6N+G" (wherein R14, R15 and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, Sθ4θrBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, Ct-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, Ci-e alkylcarbonyl, -CH=NOH, -CH2NHOH,
-C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 1-c In another more preferred first embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14R15N- (wherein Rw and R15 are each independently hydrogen or Cι-e alkyl), Rt4Ri5Ri6N+G~ (wherein R14, R15 and Ri6 are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t- butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, -CH=NOH, -CH2NHOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or C1-6 alkyl), -O(CH2)kORιs- (wherein Ri8 is hydrogen or C1-6 alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(CORi9)OH( wherein R19 and R20 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs through Rs each independently represents hydrogen, Ci-e alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -
CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH2)ι-, -(CH=CH)j-, -(CH2CH2O)j- or -(CH2CH2N)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, G-β alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), R14 15N- (wherein Rw and Ris are each independently hydrogen or Ci-β alkyl), Rι4Ri5RiδN+G~ (wherein Rw, R15 and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, Ct-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C1-6 alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR7 (wherein Rn is hydrogen or Ci-e alkyl), - O(CH2)jORi8- (wherein Ris is hydrogen or C1-6 alkyl, and j is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Ri3, R12 represents hydroxyl, G-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -
NRi9OH(wherein R19 represents a hydrogen, C1-6 alkyl, G3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein R14 and R15 are each independently hydrogen, hydroxyl or O-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, Cι-6 alkyl, C3-7 cycloalkyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein R14 and R15 are each independently hydrogen or Ci-β alkyl), Ri4Ri5RiβN+G~ (wherein Rw, R15 and Ri6 are each independently hydrogen, Ci-e alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, O-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t- butylsilyloxy, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CH2NHOH, -
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHRn (wherein Rn is hydrogen or Ci-β alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or Ci-β alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, (1) when Ri through Rt are H, X is not a -NH-CH2- or -CH2-NH- ; (2) when Rt = R2 = H, X is not -CO-NH-; (3) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-; (4) when X =-CO-O-, Y = -O-CO-, m=0, n = 0 and U is a 1,4-benzene, a 1,4-benzocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13; (5) when Ri through Rs are H, X = -CO-O-, m=n= l, U = 1,4-benzene,
Y=-O-CO-, Q is not 4-boronophenyl; (6) when Ri through Rs are H, X = -CO-O-, m=n=l, U = 1,3-benzene, Y=-O-CO-, Q is not 4-boronophenyl; (7) when Ri through Rs are H, X = -CO-O-, m=n= l, U = 1,2-benzene, Y=-O-CO-, Q is not 4-boronophenyl; (8) when Ri through Rtare H, X = -NH-SO2-, m=n=0, U = 4-methoxy- 1,3-benzene, Y=-N=N-, Q is not 4-(dimethylamino)-l-naphthalenyl; and (9) when Ri is amino, R2 through Rt are H, X= Y = -N=N-, m=n=0, U is 1,4-naphthalene, Q is not 3-boronophenyl. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
-CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, - In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 1-d In another more preferred embodiment of the first embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, C1-6 alkoxy, RwRisN- (wherein Ru and Ris are each independently hydrogen, C1-6 alkyl or benzyl), Rι4RιsRi6N+G" (wherein Rι , R15 and Riβ are each independently hydrogen, Ci-c alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Cι-6 alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CH2NHOH, - -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl); R> through Rs each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0 or 1; X and Y are each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH2 or -(CH=CH)j(wherein i = 0, 1, 2, 3 or 4 and j = 0 or 1),
-CHR9- [wherein R9 represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, Ci-β alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or C1-6 alkyl), RuRιsRi6N+G~ (wherein Ru, Ris and Riδ are each independently hydrogen, Ci-e alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3,
-SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), - NRi9OH(wherein R19 represents a hydrogen, Cι-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, Ci-β alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-β alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ct-β alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, Cι-6 alkylcarbonyl, -CH=NOH, -CH2NHOH,
-C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl); with the proviso that, (1) when Ri through Rt are H, X is not a -NH-CH2- or -CH2-NH-; (2) when Ri = R2 = H, X is not -CO-NH-; (3) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-; (4) when X =-CO-O-, Y = -O-CO-, m=0, n = 0 and U is a 1,4-benzene, a
1 ,4-benzocyclic alkene or a 1 ,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13; (5) when Ri through Rs are H, X = -CO-O-, m=n= l, U = 1,4-benzene, Y=-O-CO-, Q is not 4-boronophenyl; (6) when Ri through Rs are H, X = -CO-O-, m=n= l, U = 1,3-benzene,
Y=-O-CO-, Q is not 4-boronophenyl; (7) when Ri through Rsare H, X = -CO-O-, m=n=l, U = 1,2-benzene, Y=-O-CO-, Q is not 4-boronophenyl; (8) when Ri through Rtare H, X = -NH-SO2-, m=n=0, U = 4-methoxy- 1,3-benzene, Y=-N=N-, Q is not 4-(dimethylamino)-l-naphthalenyl; and (9) when Ri is amino, R2 through Rtare H, X=Y = -N=N-, m=n=0, U is 1,4-naphthalene, Q is not 3-boronophenyl. In this particular embodiment, each cyclic alkene is independently a structure contaimng 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (1) are set forth in Table 1 below.
Table 1: Representative Compounds in Formula (1):
Table 1 (continued)
A most preferred compounds in Formula (1) is HO_ „OH tf- FL-103
Additional compounds in Formula (1) are:
Second Preferred Embodiment In a second preferred embodiment, the compounds are described by formula (2):
wherein Rt through Rs, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 2-a In a more preferred second embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and R15 are each independently hydrogen or C1-6 alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, Ci-e alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-Z-butylsilyloxy, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Cι-6 alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or Ci-e alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, Ct-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> through Rs each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO- O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(C )i-, -(CH=CH)j-, -fCHiCϊhO or -(CH2CH2N)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rw, and each Rio independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, C1-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-δ alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, C1-6 alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, Cι-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CEbNHOH, -C(CH3) =NOH, -C(OH) =NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-β alkyl), -O(CH2)jORιs- (wherein Ris is hydrogen or Ct-β alkyl, and j is 1, 2 or 3),
-CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents Ci-β alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, Ct-β alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-δ alkyl), Ri4RιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, Cι-6 alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, ,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-e alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or Ci-β alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH( wherein R19 through R21 each independently represents a hydrogen, Ci- e alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 2-b In another more preferred second embodiment, Ri through R4 each independently represents hydrogen, Ci-δ alkyl, C3-7 cycloalkyl, C1-6 alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, Ci-β alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, G-δ alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, Ci-e alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - SO2CH3,
Rs through Rs each independently represents hydrogen, Ci-δ alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH=CH-,
-NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH∑); or -(CH=CH)j(wherein i = 0, 1, or 2, or 3 and j = 0 or 1), -CHR9- [wherein R9 represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, C alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C1-6 alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -
-SO2NH2, -CONR19OH or -CHR2oN(COR>ι)OH (wherein R19 through R2i each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, C alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2t)OH (wherein R19 through R21 each independently represents a hydrogen, C1-6 alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 2-c In a more preferred second embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form O3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO- O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH2)i-, -(CH=CH)j-, -(C CH∑O))- or -(CH2CH2N)j- (wherein i =
0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherem the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-β alkyl), -O(CH2)jORts- (wherein Ris is hydrogen or Ci-e alkyl, and j is 1, 2 or 3),
-CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHRuCORi2θr -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH) =NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, Ci- δ alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, (1) when Ri through R4 represent hydrogen, X is not -NH-CO-, -NH-SO2-, -NH- (2) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-; (3) when X =-CO-O-, Y = -O-CO-, m=0, n = 0 and U is a 1,3-benzene, 1,4- benzene, a 1,3-benzocyclic alkene, a 1,4-benzocyclic alkene, a 1,3-benzoheterocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents Rn; (4) when Rt is borono, Ri through R3 and Rs through Rs are H, X = -CO-NH- , Y=
-CO-O-, m=n= l, U = -CH2-CH2-CH2-, Q is not 2, 5-dioxo-l -pyrrolidinyl; and (5) when R3 is borono, Ri. R2 and Rs through Rs are H, X = -CO-NH-, Y=-CO-
O-, m=n=l, U = -CH2-CH2-CH2-, Q is not 2, 5-dioxo-l -pyrrolidinyl. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 2-d In another more preferred second embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, C1-6 alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRisRiβN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, », halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH=CH-, -NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH2 or -(CH=CH)j(wherein i = 0, 1, 2, or 3 and j = 0 or 1),
-CHR9- [wherein R> represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each mdependently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -
-SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic atkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, Ci-β alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONRwOH or -CHR>oN(COR2i)OH (wherein Ri9 through R21 each independently represents a hydrogen, Ci-e alkyl, trifluoromethyl or benzyl); with the proviso that, (1) when Ri through Rt represent hydrogen, X is not -NH-CO-, -NH-SO2-, -NH- (2) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-; (3) when X =-CO-O-, Y = -O-CO-, m=0, n = 0 and U is a 1,3-benzene, 1,4- benzene, a 1,3-benzocyclic alkene, a 1,4-benzocyclic alkene, a 1,3-benzoheterocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13; (4) when Rt is borono, Ri through R3 and Rs through Rs are H, X = -CO-NH-, Y= -CO-O-, m=n=l, U = -CH2-CH2-CH2-, Q is not 2,5-dioxo-l-pyrrolidinyl; and (5) when R3 is borono, Rt, R2 and Rs through Rs are H, X = -CO-NH-, Y=-CO- O-, m=n= l, U = -CH2-CH2-CH2-, Q is not 2,5-dioxo-l-pyrrolidinyl. In this particular embodiment, each cyclic alkene is independently a structure contaimng 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, the heterocyclic alkene means a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (2) are set forth in Table 2 below. Table 2: Representative Compounds in Formula (2):
Table 2 (continued)
Most preferred compounds in Formula (2) are:
Additional compounds in Formula (2) are:
Third Preferred Embodiment In a third preferred embodiment, the compounds are described by formula (3): wherein Ri through Rs, m, n, Q, U, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 3 -a In a more preferred third embodiment, Ri through R4 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; O 2005 0
X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -COCK
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH2)ι-, -(CH=CH)j-, -(CH2CH2O)j- or -(CltCILN))- (wherein i =
0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-6 alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CEb)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3),
-CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through Rn each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHRnCORi2 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherem R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl,. and k is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, Ci- e alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 3-b In another more preferred third embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl,
Ci-δ alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, O 2005/041904
halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH=CH-, -NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH- or -NH-SO2-; U represents-(CH2> or (wherein i = 0, 1, 2 or 3 and j = 0 or 1), - CHR9- [wherein R9 represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5Ri6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein Rw through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHRuCORι2 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, C alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or , -CHR>oN(COR-i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO- or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 3-c In another more preferred third embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each O 2005/041904
independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two s, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO- O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CEb)ι-, -(CH=CH)j-, -(CH2CH2θ)j- or -(CH2CH2N)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted wi /th one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, O 2005/041904
trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHRn (wherein Rn is hydrogen or CM alkyl), -O(CH2)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHRuCORi2θr -CHRuCORi2 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2 ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR>oN(COR2i)OH( wherein R19 through R21 each independently represents a hydrogen, Ci- 6 alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that , (1) when Ri through Rtare H, X is not -CH2-NH-; and (2) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-. O 2005/041904
In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or
In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 3-d In another more preferred third embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRi6N+G" (wherein Rw, Ris and Ri6 are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH=CH-,
-NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH- or -NH-SO2-; U represents-(CH2)i or -(CH=CH)j(wherein i = 0, 1, 2 or 3 and j = 0 or 1), - CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5Ri6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Ri3, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONRwOH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that , (1) when Ri through Rt are H, X is not -CH2-NH-, and (2) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-. In this particular embodiment, each cyclic alkene is independently a structure contaimng 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by ύ bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO- or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (3) are set forth in Table 3 below.
Table 3: Representative Compounds in Formula (3):
Table 3 (continued)
The most preferred compounds in Formula (3) are:
Fourth Preferred Embodiment In a fourth preferred embodiment, the compounds are described by formula (4):
wherein Ri through Re, m, n, Q, and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 4-a In a more preferred fourth embodiment, Ri through R4 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-e alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-β alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or C alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CH=CH-CO-O-, -CH=CH-CO-NH-, -
CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-
-CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHRnCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), . -O(CH2 ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 4-b In another more preferred fourth embodiment, Rt through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G~ (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - Rs and Rδ each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH-CO-, -CH=N-, -CH=CH-, -NH-CH2-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 4-c In another preferred fourth embodiment, Ri through R each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl,
CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -Ofe-CIL-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-
-CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or C alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Rie are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, (1) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (2) when Ri through Rtare H, m=n=0, X is not -CO-O-; (3) when Ri = R2 = H, X is not -CO-NH-; (4) when X =-CO-O-, Rs = H, Re = H, m=l and n = 0, Q is not a benzene, a benzocyclic alkene or a benzoheterocychc alkene, which may be substituted with one or more substituents RB; (5) when X =-CO-O-, m=0 and n = 0, Q is not a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13; (6) when Ri through R4 are H, X = -CO-O- and m=n=0, Q is not 2,5-dioxo-l- pyrrolidinyl; (7) when Ri through Rtare H, X = -CO-O- and m=n=0, Q is not cyclohexyl; (8) when Ri through Rt are H, X = -O-CO- and m=n=0, Q,is not cyclopropyl; (9) when Ri through Rtare H, X = -NH-SO2-, m=n=0, Q is not 4-(4,5- dihydro-3-phenyl-lH-pyrazol-l-yl)phenyl; (10) when Ri through R4 are H, X = -NH-SO2-, m=n=0, Q is not 5- (dimethylamino)- 1 -naphthalenyl ; (11) when Ri through Rt are H, X —NH-CH2- and m=n=0, Q is not phenyl; (12) when Ri through Rtare H, X = -NH-CO-, m=n=0, Q is not phenyl; (13) when Ri through Rtare H, X = -NH-CO- and m=n=0, Q is not phenyl; (14) when Ri through Rt are H, X = -NH-CO-, m=n=0, Q is not 4-chloro-3-(4- methyl- 1 -piperazinyl)phenyl ; (15) when Ri through Rt are H, X = -NH-CO-, m=n=0, Q is not 4-methoxy-3-
(4-methyl- l-piperazinyl)pheny 1 ; (16) when Ri through Rtare H, X = -NH-CO-, m=n=0, Q is not 3-methoxy-4- (4-methyl-l-piperazinyl)phenyl; (17) when Ri, R3 through Re are H, R- is methoxyl, X = -NH-CO-, m=2, n=0, Q is not phenyl; (18) when Ri through Rt are H, X = -N=N-, m=n=0, Q is not 4- (dimethy lamino)pheny 1 ; (19) when Ri is amino, R2 through R4are H, X = -N=N-, m=n=0, Q is not 1- naphthalenyl; (20) when Ri is amino, R2 through Rtare H, X = -N=N-, m=n=0, Q is not 4- carboxyphenyl; and (21) when Ri through Rtare H, X = -N=N-, m=n=0, Q is not 2-hydroxy-l- naphthalenyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
-CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -
In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 4-d In another more preferred fourth embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyanό, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - Rs and Rδ each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH-CO-, -CH=N-, -CH=CH-, -NH-CH2-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHRuCORι2 or -CHR11COR12 [wherein Rn represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR>oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-e alkyl, trifluoromethyl or benzyl); with the proviso that, (1) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (2) when Ri through Rt are H, m=n=0, X is not -CO-O-; (3) when Ri = R2 = H, X is not -CO-NH-; (4) when X =-CO-O-, Rs = H, Re = H, m=l and n = 0, Q is not a benzene, a benzocyclic alkene or a benzoheterocychc alkene, which may be substituted with one or more substituents Rq; (5) when X =-CO-O-, m=0 and n = 0, Q is not a benzene, a benzocyclic alkene or a benzoheterocychc alkene, which may be substituted with one or more substituents Rn; (6) when Ri through Rt are H, X = -CO-O- and m=n=0, Q is not 2,5-dioxo-l- pyrrolidinyl; (7) when Ri through Rtare H, X = -CO-O- and m=n=0, Q is not cyclohexyl; (8) when Ri through Rtare H, X = -O-CO- and m=n=0, Q is not cyclopropyl; (9) when Rt through Rtare H, X = -NH-SO2-, m=n=0, Q is not 4-(4,5- dihy dro-3 -phenyl- 1 H-pyrazol- 1 -yl)pheny 1 ; (10) when Ri through Rt are H, X = -NH-SO2-, m=n=0, Q is not 5-
(dimethylamino)- 1 -naphthalenyl ; (11) when Ri through Rtare H, X =-NH-CH2- and m=n=0, Q is not phenyl; (12) when Ri through Rtare H, X = -NH-CO-, m=n=0, Q is not phenyl; (13) when Ri through Rtare H, X = -NH-CO- and m=n=0, Q is not phenyl; (14) when Ri through R4 are H, X = -NH-CO-, m=n=0, Q is not 4-chloro-3-(4- methyl- 1 -piperazinyl)phenyl ; (15) when Ri through Rtare H, X = -NH-CO-, m=n=0, Q is not 4-methoxy-3- (4-methyl- 1 -piperazinyl)phenyl ; (16) when Ri through Rtare H, X = -NH-CO-, m=n=0, Q is not 3-methoxy-4- (4-methy 1- 1 -piperazinyl)phenyl ; (17) when Ri, R3 through Re are H, R2 is methoxyl, X = -NH-CO-, m=2, n=0, Q is not phenyl; (18) when Ri through R4 are H, X = -N=N-, m=n=0, Q is not 4- (dimethylamino)pheny 1 ; (19) when Ri is amino, R2 through R are H, X = -N=N-, m=n=0, Q is not 1- naphthalenyl; (20) when Ri is amino, R2 through Rtare H, X = -N=N-, m=n=0, Q is not 4- carboxyphenyl; and (21) when Ri through R are H, X = -N=N-, m=n=0, Q is not 2-hydroxy-l- naphthalenyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (4) are set forth in Table 4 below. Table 4: Representative Compounds in Formula (4):
Table 4 (continued)
-81-
-82-
-83- A most preferred compound in Formula (4) is:
FL-104
Additional compounds in Formula (4) are:
5. Fifth Preferred Embodiment In a fifth preferred embodiment, the compounds are described by formula (5): OH HO- (5) R4- -(CH2)n X (CR5R6)m-Q
wherein Ri through Re, m, n, Q, and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 5-a In a more preferred fifth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -CH2-; -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-
-CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHRnCORi2 or -CHR11COR12 [wherein Ru represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherein O 2005/041904
R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N- (wherein Rw and R15 are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G' (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2 ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR>oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 5-b In another more preferred fifth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - Rs and Rδ each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, , hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH-
CO-, -CH=N-, -NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-or -NH-SO2-; Q represents -CH2CHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 5-c In another more preferred fifth embodiment, Ri tlirough Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, . benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORts- (wherein Ris is hydrogen or C alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-
-CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 Λ represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each mdependently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH( wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, (1) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (2) when R2 and R3 are H, m=n=0, X is not -CH=CH-; (3) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -CO-O-; (4) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -NH-CO-; (5) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -O-CO-; (6) when Rs and Re = H, m= 1, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -CO-O-; (7) when Ri through Rtare H, X = -CO-NH-, m=n=0, Q is not phenyl; (8) when Ri and R2 are H, R3 is F, Rt is methyl, X = -CO-NH-, m=n=0, Q is not cyclopropyl; (9) when Ri through Re are H, X = -CO-NH-, m=3, n=0, Q is not phenyl; (10) when Ri through Re are H, X = -CH2-CH-, m= 1, n=0, Q is not phenyl; (11) when Ri through Rtare H, X = -NH-CH2-, m=0 and n= l, Q is not phenyl; (12) when Ri through R4 are H, X = -NH-CH2-, m=0 and n=0, Q is not pentafluorophenyl; (13) when Ri through Rt are H, X = -CH=CH-, m=0 and n=0, Q is not phenyl; and O 2005/041904
(14) when Ri tlirough Rtare H, X = -CH=CH-, m=0 and n=0, Q is not 2- boronophenyl. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 5-d In another more preferred fifth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-δ alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - R> and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, , hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH- CO-, -CH=N-, -NH-CH2-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-or -NH-SO2-; Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, C alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), Rt4RιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-δ alkyl, trifluoromethyl or benzyl); with the proviso that, (1) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (2) when R2 and Rs are H, m=n=0, X is not -CH=CH-; (3) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -CO-O-; (4) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -NH-CO-; (5) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents Rn, X is not -O-CO-; (6) when Rs and Re = H, m= 1, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13,
X is not -CO-O-; (7) when Ri through Rtare H, X = -CO-NH-, m=n=0, Q is not phenyl; (8) when Ri and R2 are H, R3 is F, Rt is methyl, X = -CO-NH-, m=n=0, Q is not cyclopropyl; (9) when Ri through Rβare H, X = -CO-NH-, m=3, n=0, Q is not phenyl; (10) when Ri through Re are H, X = -CH2-CH-, m= 1, n=0, Q is not phenyl; (11) when Ri through Rtare H, X = -NH-CH2-, m=0 and n= l, Q is not phenyl; (12) when Ri through Rt are H, X = -NH-CH2-, m=0 and n=0, Q is not pentafluorophenyl ; (13) when Ri through Rt are H, X = -CH=CH-, m=0 and n=0, Q is not phenyl; and (14) when Ri through Rtare H, X = -CH=CH-, m=0 and n=0, Q is not 2- boronophehyl. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH.-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (5) are set forth in Table 5 below.
O 20
Table 5: Representative Compounds in Formula (5):
O 200
Table 5 (continued)
The most preferred compounds in Formula (5) are:
FL-065 FL-067 FL-068 FL-069
FL-071 FL-072 FL-073 FL-074
FL-075 FL-080 FL-081 FL-082
FL-083 FL-084 FL-085 FL-086
FL-087 FL-088 FL-089 FL-090
FL-107 FL-108 FL-109 FL-110
113 FL-114 FL-132 FL-133
Additional compounds in Formula (5) are:
FL-1010 FL-1201
6. Sixth Preferred Embodiment In a sixth preferred embodiment, the compounds are described by formula (6):
wherein Ri through Re, m, n, Q and X can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 6-a In a more, preferred sixth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each mdependently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Rδ each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH- CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORι8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring t may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 6-b In another more preferred sixth embodiment, Ri through Rt each independently represents hydrogen, C alkyl, C3-7 cycloalkyl, C alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH-CO-, -CH=N-, -CH=CH-, -NH-CH2-, -CH2-NH-, -CH2-O-, -SO2-O-, -O-SO2-, -SO2-NH-, or - Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, R15 and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 6-c In another more preferred sixth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Rδ each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH- CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHRnCORi2θr -CHRnCORι2 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, Rι2 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G~ (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, (1) when Ri through Rt are H, X is not -CH2-NH-; (2) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (3) when Ri through Rtare H, X = -NH-CO-, m=0 and h=l, Q is not phenyl; (4) when Ri through Rtare H, X = -NH-CO-, m=0 and n=0, Q is not phenyl; (5) when Ri through Rtare H, X = -NH-CH2-, m=0 and n=l, Q is not phenyl; (6) when Ri through Re are H, X = -NH-CH2-, m=2 and n= l, Q is not phenyl; (7) when Ri through Rt are H, X = -NH-CH2-, m=0 and n= 1, Q is not 10- (hydroxymethyl)-9-anthracenyl; (8) when Ri through Rtare H, X = - NH-CH2-, m=n=0, Q is not phenyl; (9) when Ri through Rsare H, X = -CH2-NH-, m=n=l, U is 1,3-benzene, Y=Z= -NH-CH2-, Q is not 2-boronophenyl; and (10) when Ri through Re are H, X = -CO-O-, m= 1 and n=0, Q is not 4- methoxyphenyl. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -
In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 6-d In another more preferred sixth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-δ alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH-CO-, -CH=N-, -CH=CH-, -NH-CH2-, -CH2-NH-, -CH2-O-, -SO2-O-, -O-SO2-, -SO2-NH-, or
Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein R and Ris are each independently hydrogen or Ci-β alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that, (1) when Ri through Rt are H, X is not -CH2-NH-; (2) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (3) when Ri through Rt are H, X = -NH-CO-, m=0 and n=l, Q is not phenyl; (4) when Ri through R4 are H, X = -NH-CO-, m=0 and n=0, Q is not phenyl; (5) when Ri through Rt are H, X = -NH-CH2-, m=0 and n= 1, Q is not phenyl; (6) when Ri through Re are H, X = -NH-CH2-, m=2 and n=l, Q is not phenyl; (7) when Ri through Rt are H, X = -NH-CH2-, m=0 and n= 1, Q is not 10- (hydroxymethyl)-9-anthracenyl ; (8) when Ri through Rtare H, X = - NH-CH2-, m=n=0, Q is not phenyl; (9) when Ri through Rsare H, X = -CH2-NH-, m=n= l, U is 1,3-benzene, Y=Z= -NH-CH2-, Q is not 2-boronophenyl; and (10) when Ri through Rβare H, X = -CO-O-, m=l and n=0, Q is not 4- methoxyphenyl. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (6) are set forth in Table 6 below.
Table 6: Representative Compounds in Formula (6):
Table 6 (continued)
The most preferred compounds in Formula (6) are:
Seventh Preferred Embodiment In a seventh preferred embodiment, the compounds are described by formula (7):
, wherein Ri through Re, m, n, Q, U, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 7-a In a more preferred seventh embodiment, Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1 ; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(CH2)i-, or -(CH2CH2N)j- (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Rie are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, C alkylcarbonyl, - CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHRnCORι2 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)] , a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 7-b In another more preferred seventh embodiment, Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRisRt6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m or n is each independently 0 or 1 ; X is -CO-O-, -CH2-O-CO-, -CO-NH-,- CH2-O-NH-, -CH2-CH2, -CH=CH-, -CH2- O-, Y is -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or
-N=N-; W is oxygen or lone-pair electrons; U represents -(CBb or -(CH=CH)j (wherein i = 0, 1, 2 or 3 and j = 0 or 1),
-CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), Rι Ri5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -
-SO2NIL2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and R15 are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CH3)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (7) are set forth in Table 7 below.
Table 7: Representative Compounds in Formula 7:
Table 7 (continued)
The most preferred compounds in Formula (7) are:
Eighth Preferred Embodiment In an eighth preferred embodiment, the compounds are described by formula (8):
wherein Ri through Re, m, n, Q, U, N, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 8-a In a more preferred eighth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(CEk)i-, -(CH=CH)r, -(CH2CH2O)j- or -(CmCEb - (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, - CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G~ (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, Ct-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
-CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 8-b In another more preferred eighth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m or n is each independently 0 or 1; X is -CO-O-, -CH2-O-CO-, -CO-NH-,- CH2-O-NH-, -CH2-CH2, -CH=CH-, -CH2- O-, Y is -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or
-N=N-; W is oxygen or lone-pair electrons; U represents -(CH2 or -(CH=CH)j (wherein i = 0, 1, 2 or 3 and j = 0 or 1), -CHR9- [wherein R> represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio] , a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -
-SO2NH2, -CONR19OH or -CHR2oN(COR2t)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rt3 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, Ci-β alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (8) are set forth in Table 8 below. - Table 8: Representative Compounds in Formula (8):
Table 8 (continued)
The most preferred compounds in Formula (8) are:
9. Ninth Preferred Embodiment In a ninth preferred embodiment, the compounds are described by formula (9):
wherein Rt through Rt, 1, m, n, P, Q, V, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 9-a In a more preferred ninth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRtsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C= , -CH2-CH= , -CH2-CH2-CH= , -CHCH3-CH= , a
C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G~ (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CI CHRiiCOR or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 9-b In another more preferred ninth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; V represents a nitrogen, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4 orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR>oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene 'or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl),
RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 9-c In another more preferred ninth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is. each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O-
CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C=, -CH2-CH=, -CH2-CH2-CH=, -CHCH3-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein
Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ct-β alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH- . In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
-CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 9-d In another more preferred ninth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl,
Ci-6 alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-β alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CIΪ3)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -
CH=CH-, -NH-CH2-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; N represents a nitrogen, , -CH2-CH2-CH=, -CHCH3-CH=, a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδΝ+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH) =NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or
-CHR2oN(COR>ι)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)] , a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH- . In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (9) are set forth in Table 9 below.
Table 9: Representative Compounds in Formula (9):
Table 9 (continued)
The most preferred compounds in Formula (9) are:
10. Tenth Preferred Embodiment In a tenth preferred embodiment, the compounds are described by formula (10):
, wherein Ri tlirough Rt, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 10-a In a more preferred tenth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-6 alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδΝ+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CIL-, - CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-β alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRnCORnor -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)] , a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 10-b In another more preferred tenth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -CH=N-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-. Y or Z is not - CO-NH or
V represents a nitrogen, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHRoN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein
Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein Ri9 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO- or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 10-c In another more preferred tenth embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl,
Ci-δ alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2 ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, ) 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CHbCHRπCORπor -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH) =NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, when Ri through Rt represent hydrogen, X is not -NH-CO- or -NH-SO2-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 10-d In another more preferred tenth embodiment, Ri tlirough Rt each independently represents hydrogen, Ct-β alkyl, C3-7 cycloalkyl, Ci-e alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, S torBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -CH=N-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-. Y or Z is not - CO-NH or V represents a nitrogen, a
Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-δ alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that, when Ri through Rt represent hydrogen, X is not -NH-CO- or -NH-SO2-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO- or -CH2-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (10) are set forth in Table 10 below.
Table 10: Representative Compounds in Formula (10):
Table 10 (continued)
Most preferred compounds in Formula (10) are:
FL-164 FL-165 Additional compounds in Formula (10) are:
11. Eleventh Preferred Embodiment In an eleventh preferred embodiment, the compounds are described by formula (11):
wherein Ri through R4, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 11-a In a more preferred eleventh embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-e alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδΝ+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R>o each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O-
CO-, -CO-NH-, -NH-CO-, -CU2-CΗ2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C=, -CH2-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy,, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHRnCORi2 or -CHR11COR12 [wherein Ru represents Ci-β alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH( wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 11-b In another more preferred eleventh embodiment, Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -CH=N-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents a nitrogen, -CHCm-CH=, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm) =NOH, -C(OH) =NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or
-CHR2oN(COR.ι)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-δ alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CmCHRuCORnor -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, - CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 11-c In another more preferred eleventh embodiment, Rt through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C = , -Cm-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or C alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1 , 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, C alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRuCORi2 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-β alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 or BF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, (1) when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-; and (2) when Ri through Rtare H, X = -CH2-NH-, l=m=n=2, V is a nitrogen, Y=Z= -NH-CH2-, P and Q is -not 2-boronophenyl at the same time. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
-CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 11-d In another more preferred eleventh embodiment, Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, 1 halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -CH=N-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents a nitrogen, -Cm-CH=, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen,„C_M alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), " trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONRwOH or -CHR>oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, C alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that, (1) when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-; and (2) when Ri through Rtare H, X = -CH2-NH-, l=m=n=2, V is a nitrogen, Y=Z= -NH-CH2-, P and Q is not 2-boronophenyl at the same time. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (11) are set forth in Table 11 below.
Table 11: Representative Compounds in Formula (11):
Table 11 (continued)
The most preferred compounds in Formula (11) are:
12. Twelfth Preferred Embodiment In a twelfth preferred embodiment, the compounds are described by formula (12):
wherein Ri through R>, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 12-a In a more preferred twelfth embodiment, Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6Ν+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBEt), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, a
C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRuCORi∑or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, C alkyl, C3-7 cycloalkyl,
CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORi8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 12-b In another more preferred twelfth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; W is oxygen or lone-pair electrons; N represents a nitrogen, -Cm-CH=, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6Ν+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or
-CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, - SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atorn(s). c. Preferred embodiment 12-c In another more preferred twelfth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O , - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. N represents nitrogen, -CH=C = , a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδΝ+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, C alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRnCORπor -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl,
CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH) =NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 12-d In another more preferred twelfth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRtsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -
CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -Cm-CH=, -Cm-Cm-CH=, -CHCH3-CH=, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, Ci-β alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(CORzι)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CmCHRuCOR or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, - SO2CH3, -SO2NH2, -CONR19OH or
-CHR2oN(COR>ι)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (12) are set forth in Table 12 below. Table 12: Representative Compounds in Formula (12):
Table 12 (continued)
The most preferred compounds in Formula (12) are:
13. Thirteenth Preferred Embodiment In a thirteenth preferred embodiment, the compounds are described by formula (13):
wherein Ri through R2, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 13-a In a more preferred thirteenth embodiment, Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-β alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδΝ+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORt9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -CH2-CH=, -Cm-Cm-CH=, -CHCH3-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, C alkyl, C3-7 cycloalkyl, C alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl,1 phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, Ct-β alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, C alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, Ci-β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, Ci-e alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR>oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 13-b In another more preferred thirteenth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -CH2-CH = , -CH2-CH2-CH = , -CHCH3-CH = , a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(CORzι)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-δ alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CmCHRuCORπor -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, - SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 13-c In another more preferred thirteenth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-β alkyl), RwRιsRiδN+G~ (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, - -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -
O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -Cm-CH=, -Cm-Cm-CH=, -CHCH3-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-β alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein
Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
-CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 13-d In another more preferred thirteenth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRtsN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -C(Cm)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -CH2-CH= , -Cm-Cm-CH= , -CHCH3-CH= , a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CmCHRuCORi2θr -CHR11COR12 [wherein Ru represents Ci-e alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, C alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, - SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (13) are set forth in Table 13 below.
Table 13: Representative Compounds in Formula (13):
Table 13 (continued)
The most preferred compounds in Formula (13) are:
14. Fourteenth Preferred Embodiment In a fourteenth preferred embodiment, the compounds are described by formula
(14):
wherein Ri through R2, 1, m, n, P, Q, N, W, X, Y, and Z can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 14-a In a more preferred fourteenth embodiment, Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδΝ+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, - C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -Cm-CH=, -Cm-Cm-CH=, -CHCH3-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRtδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR9OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G~ (wherein Rw, Ris and Rtβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORi8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 14-b In another more preferred fourteenth embodiment, Ri and Rz each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(Cm)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -CH2-CH= , -Cm-Cm-CH= , -CHCE -CH= , a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SOtorBEt), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5Rt6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, - SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-e alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). c. Preferred embodiment 14-c In another more preferred fourteenth embodiment, Ri and Rz each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, SO4orBF , trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORt9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -
O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -Cm-CH=, -Cm-CH2-CH=, -CHCH3-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORi8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein
Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH( wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form
-CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or - cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). d. Preferred embodiment 14-d In another more preferred fourteenth embodiment, Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(Cm)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - so2cm, or 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -Cm-CH= , -Cm-Cm-CH= , -CHCm-CH= , a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Ri6 are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR_oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, - SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-. In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). Non-limiting representative compounds of formula (14) are set forth in Table 14 below.
Table 14: Representative Compounds in Formula (14):
Table 14 (continued)
The most preferred compounds in Formula (14) are:
15. Fifteenth Preferred Embodiment In a fifteenth preferred embodiment, the compounds are described by formula (15):
wherein Ri through Re, m, n, Q, U, W, X, and Y can vary in order to optimize affinity, activity, absorption, distribution, metabolism, excretion, pharmacokinetic, toxicological' and other properties required for their use as orally deliverable pharmaceuticals. a. Preferred embodiment 15-a In a more preferred fifteenth embodiment, Ri and R2 each independently represents hydrogen, C alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRiβN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR9OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -Cm~O-, -NH-CH2-, -CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(Cm)ι-, -(CH=CH)j-, -(CmcmO)j- or -(CmCH2N)j- (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, - CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3),
-CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CmCHRuCORi∑or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, Ru represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene br a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy (e.g., n- butoxy, i-butoxy, sec-butoxy), RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF , trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR>oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). b. Preferred embodiment 15-b In another more preferred fifteenth embodiment, Rt and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(Cm)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m or n is each independently 0 or 1; x is -CO-O-, -CH2-0-CO-, -co-NH-,- cm-o-NH-, -cm-cm, -CH=CH-, -c -
O-, Y is -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-Cm-, -CH2O-, -NH-Cm-, -CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or
-N=N-; W is oxygen or lone-pair electrons; U represents -(Cm or -(CH=CH)j (wherein i = 0, 1, 2 or 3 and j = 0 or 1),
-CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -
-SO2NH2, -CONR19OH or -CHR2oN(COR2t)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl,
C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rn, R12 represents hydroxyl, CM alkoxy (e.g., n-butoxy, i-butoxy, sec-butoxy), -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rn, and each Rn independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR>oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl). In this particular embodiment, each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one • double bond. One, two, or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, - NH-, -S-, -SO2-, -CO-, or -Cm-). In this particular embodiment, each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s). • Non-limiting representative compounds of formula (15) are set forth in Table 15 . below.
Table 15: Representative Compounds in Formula (15):
Table 15 (continued)
The most preferred compounds in Formula (15) are:
Proteases The compounds of the present invention can be used to inhibit any coronavirus proteases. In yet another embodiment, such protease has one or more serine or threonine residues at or near the catalytic site. ' In a preferred embodiment, such protease has two or more serine or threonine residues at or near the catalytic site. In a more preferred embodiment, such protease is a cysteine protease, that is , the catalytic residue of the protease is a cysteine. In a most preferred embodiment, such protease is a 3CLpro.
Coronaviruses The boronic acid-based compounds of the present invention can be used to treat infections caused by various viruses and can be used to inhibit protease(s) of various viruses. These various viruses are described in, for example, Fields Nirology (4th Edition, Lippincott Williams & Wilkins (2001)). In one embodiment, the virus belongs to the Coronavindae family. The Coronavindae family includes two genera, coronavirus and torovirus, which share many features of genome organization and replication strategy but have different virion morphology and genome lengths. The viral envelopes are studded with long, petal shaped spikes, giving coronaviruses the appearance of a crown (Latin, corona), and the nucleocapsids are long, flexible helices. Other characteristics that define Coronavindae include the 3'-coterminal, nested-set structure of the mRNAs, unique RNA transcription strategy, genome organization, nucleotide sequence homology, and the properties of their structural proteins. In one particular embodiment, the virus is a coronavirus. Cornoaviruses, a genus in the family Coronaviradae, are large, enveloped, positive-stranded RNA viruses that cause highly prevalent diseases in humans and domestic animals. They have the largest genomes of all RNA viruses and replicate by a unique mechanism, which results in a high frequency of recombination. Virions mature by budding at intracellular membranes, and infection with some coronaviruses induces cell fusion. Coronaviruses were first recognized as a distinct virus group by their characteristic virion morphology in negatively stained preparations. Most coronaviruses can be divided into three serologically distinct groups, although SARS-associated virus does not fit into any of these three known groups. Within each serogroup, the viruses are classified according to their natural hosts, nucleotide sequences, and serologic relationships. Most coronaviruses naturally infect only one animal species or, at most, a limited number of closely related species. Virus replication in vivo can be either disseminated, causing systemic infections, or restricted to a few cell types, often the epithelial cells of the respiratory or enteric tracts and macrophages, causing localized infections. Group I coronaviruses include, for example, HCoV-229E (human respiratory coronavirus), TGEV (porcine transmissible gatroenteritis virus), PRCoN (porcine respiratory coronavirus), CCoN (canine coronavirus), FECoN (Feline enteric coronavirus), FIPN (feline infectious peritonitis virus), and RbCoN (rabbit coronavirus). Group II coronaviruses include, for example, HCoN-OC43 (human respiratory coronavirus), MHV (murine hepatitis virus), SDAN (sialodacryoadenitis virus), HEV (porcine hemagglutinating encephalomyelitis virus), and BCoV (bovine coronavirus). Group III coronaviruses include, for example, IBV (avain infectious bronchitis virus) and TCoV (turkey coronavirus). The SARS-associated coronavirus genome appears to be closer to the murine, bovine, porcine, and human coronaviruses in Group Iϊ and avian coronavirus IBV in Group I. Non-limiting examples of the coronavirus include SARS-associated virus, rat coronavirus (ATCC Nos. VR-1410 (Sialodacryoadenitis virus, deposited as rat coronavirus), and VR-882), murine hepatitis virus (ATCC Nos. VR-1426, VR-246, VR- 261, VR-764, VR-765 (murine hepatitis virus deposited as mouse hepatitis virus), and VR- 766), human enteric coronavirus (ATCC No. VR-1475), feline coronavirus (ATCC Nos. VR-2004, VR-2009. VR-2125, VR-2126, VR-2127, VR-2128, VR-2201, VR-2202, VR- 867, VR-989, and VR-990), canine coronavirus (ATCC Nos. VR-2068 and VR-809), infectious bronchitis virus (ATCC Nos. VR-21, VR-22, VR-817, and VR-841), human coronavirus 229E (ATCC No. VR-740), transmissible gastroenteritis virus (porcine respiratory coronavirus) (ATCC Nos. VR-743 and VR-763), human coronavirus OC43 (ATCC No. VR-759), bovine coronavirus (calf diarrheal coronavirus) (ATCC No. VR- 874), rat coronavirus (ATCC No., VR-882); turkey coronavirus (ATCC No. VR-911), rabbit coronavirus (ATCC No. VR-920), and transmissible gastroenteritis virus (ATCC No. VR-2384). (
Salts and Derivatives Various pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility- altering derivatives of the active compound also are encompassed by the present invention. The present invention further includes all individual enantiomers, diastereomers, racemates, and other isomer of the compound. The invention also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of this compound. Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution, based on the disclosure provided herein. Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyravic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic or inorganic ligands, such as quaternary ammonium salts. Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-memylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate salts of the compound of the present invention. Prodrugs and active metabolites of compounds disclosed herein are also within the scope of the invention. A prodrug is a pharmacologically inactive compound that is converted into a pharmacologically active agent by a metabolic transformation. In vivo, a prodrug is acted on by naturally occurring enzyme(s) resulting in liberation of the pharmacologically active agent. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. An active metabolite is a compound which results from metabolism of another compound after administration of the latter to a subject. Metabolites can be identified by techniques well-known in the art.
Formulation and Administration Suitable dosage forms include but are not limited to oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra- uterille administration, and other dosage forms for systemic delivery of active ingredients. In a preferred embodiment, the dosage form is suitable for injection. To prepare such pharmaceutical dosage forms, one or more of the aforementioned compounds of formulae (A), (B) and (1)-(15), are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of foπns depending on the form of preparation desired for administration. For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed. ' In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques. In some applications, it may be advantageous to utilize the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides. Treatment methods of the present invention using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught. A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine. A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol. ) Formulations suitable for parenteral administration usually comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form. Parenteral administration may comprise any suitable form of systemic delivery or delivery directly to the CNS. Administration may for example be intravenous, intra- arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality. Nasal and other mucosal spray formulations (e.g. inhalable forms) can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like. Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids. Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer. In addition to the aforementioned ingredients, formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like. The formulation of the present invention can have immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art. The subject is preferably an animal, including, but not limited, to an animal such a cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, etc., and is more preferably a mammal, and most preferably a human.
EXAMPLES The following examples illustrate the invention, but are not limiting.
EXAMPLE 1. Synthesis of Select Compounds 1.1 General Procedure A: Synthesis of boronobenzoic acid esters i, (COCl)2, DMF, CH2C12, rt, overnight ii, Et3N, CH2C12, rt, overnight
In step (i) of general procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of carboxyl boronic acid derivative A-1 (0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride A-2 as a yellow solid, which was used without further purification. In step (ii), a solution of the acid chloride A-2 (0.2 mmol, obtained from step (i) above) in 5 mL of anhydrous CH2CI2 was added dropwise to an ice-cold solution of A-3, anhydrous triethyl amine (42 μL, 0.3 mmol) and 10 mL of anhydrous CH2CI2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was then dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHC03,.. saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10). The product yielded from step (ii) is A-4.
3-(4-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-061)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with/>-nitroρhenol (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 42 mg (84% yield) of the desired compound as a white powder, mp: 205-207°C 1H-NMR(300MHz, 5%D2O in d6-OMSO): δ 7.61-7.66 [m, 2H, Ar-H], 8.30-8.35 [m, 2H, Ar-H], 8.78-8.89 [m, 3Η, Ar-H].
3-(2-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-062)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ø-nitrophenol (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 36 mg (72% yield) of the desired compound as a pale yellow powder, mp: 128-130°C. 1H-NMR(300MHz, 5%D2O in d6- DMSO): 7.52-7.71 [m, 2H, Ar-H], 7.81-7.94 [m, 1Η, Ar-H], 8.13-8.24 [m, 1Η, Ar-H], 8.70-8.93 [m, 3Η, Ar-H].
3-(3-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-063)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2O2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with m-nitrophenol (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (82% yield) of the desired compound as a light yellow crystal, mp: 185-187°C 1H-NMR(300MHz, 5%D2O in d6- DMSO): J7.72-7.81 [m, 2H, Ar-H], 8.15-8.29 [m, 2Η, Ar-H], 8.76-8.89 [m, 3Η, Ar-H]. 3-(4-MethoxyphenoxycarbonylV5-nitrophenylboronic acid (FL-064)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with -methoxyphenol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (81% yield) of the desired compound as a white needle, mp: 67°C. 1H-NMR(300MHz, 5%D2O in d6-OMSO): δ 3.74 [s, 3H, OCHj], 6.93-6.99 [m, 2Η, Ar-H], 7.19-7.24 [m, 2Η, Ar-H], 8.72-8.87 [m, 3Η, Ar- HJ.
3-(4-Ethoxycarbonylphenoxycarbonyl)-5-nitrophenylboronic acid fFL-065)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ethyl 4-hydroxybenzoate (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 51 mg (94% yield) of the desired compound as a white powder, mp: 230-232°C. 1H-NMR(400MHz, 5%D2O in d6- DMSO): 1.31 [t, 2H, CH2CH3], 4.30 [q, 3H, CH2CH5], 7.50 [d, 2Η, Ar-H], 8.05 [d, 2Η, Ar- H], 8.78-8.90 [m, 3Η, Ar-H]. 3-f2-Oxo-benzo[l ,3]oxathiol-6-oxycarbonyl)-5-nitrophenylboronic acid (FL-067)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 6-hydroxy-l,3-benzoxathiol- 2-one (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 50 mg (92% yield) of the desired compound as a white powder, mp: 145-147°C. 1H-NMR(300MHz, 5%D2O in ^6-DMSO): J7.28-7.36 [m, IH, Ar-H], 7.56-7.64 [m, 1Η, Ar-H], 7.78-7.86 [m, 1Η, Ar-HJ, 8.72-8.86 [m, 3Η, Ar-H].
3-(2-Cyanophenoxycarbonyl)-5-nitrophenylboronic acid (FL-068)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-hydroxybenzonitrile (18 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (92% yield) of the desired compound as a white powder, mp: 248-250°C. 1H-NMR(400MHz, 5%D2O in d6-
DMSO): J7.48-7.57 [m, IH, Ar-H], 7.62-7.69 [m, 1Η, Ar-H], 7.78-7.89 [m, 1Η, Ar-H], 7.96- 8.01 [m, 1Η, Ar-H], 8.83-8.94 [m, 3Η, Ar-H].
3 - 2-Chloro-6-mtrophenoxycarbonyl)-5-nitrophenylboronic acid (FL-069) HO^OH
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-6-nitrophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (71% yield) of the desired compound as a yellow needle, mp: 179°C. 1H-NMR(300MHz, 5%D2O in d6- DMSO): J7.54-7.72 [m, IH, Ar-H], 8.01-8.24 [m, 2Η, Ar-H], 8.65-8.94 [m, 3Η, Ar-H].
3 -(2-Ethoxycarbonyl-phenoxycarbonyl)-5-nitrophenylboronic acid (FL-071 )
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ethyl salicylate (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (64% yield) of the desired compound as a yellow semisolid. IH-NMR(300MHz, 5%D2O in d6-DMSO): J 1.24 [t, 2H, CH CH3], 4.31 [q, 3H, CH2CHj], 7.41-7.57 [m, 2Η, Ar-H], 7.81-8.05 [m, 2Η, Ar-H], 8.67- 8.93 [m, 3Η, Ar-H].
3-(2-Chlorophenoxycarbonyl)-5-nitτophenylboronic acid (FL-072)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with o-chlorophenol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 44 mg (90% yield) of the desired compound as a white powder, mp: 138-140°C. 1H-NMR(300MHz, 5%D2O in d6-DMSO): δ 7.38-7.78 [m, 4H, Ar-H], 8.71-9.04 [m, 3Η, Ar-HJ.
3-(2-Methylphenoxycarbonyl)-5-nitro-phenylboronic acid (FL-073)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with ø-cresol (16 mg, 0.15 mmol) 15 according to general procedure A, step (ii), to give 40 mg (89% yield) of the desired compound as a yellow powder, mp: 175°C(dec). IH-NMR(300MHz, 5%D20 in d6-DMSO): δ 2.17 [t, 3H, CH3], 7.21-7.40 [m, 3H, Ar-H], 8.15-8.22 [m, 1Η, Ar-HJ, 8.65-8.91 [m, 3Η, Ar- HJ. 0 3-(2-Methoxylphenoxycarbonyl)-5-nitrophenylboronic acid (FL-074)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then5 evaporated to dryness. The product obtained was reacted with guaiacol (19 mg, 0.15 mmol) O 2005/041904
according to general procedure A, step (ii), to give 44 mg (92% yield) of the desired ccoommppoouunndd aass aa yyeellllooww sseemmiissoolliidd.. IIHΗ--NNMMRR((330000MMHΗzz,, 55%%DD:2O in d6-OMSO): J3.69[s, 3H, OCHjJ, 7.46-8.03 [m, 4Η, Ar-HJ, 8.64-8.97 [m, 3Η, Ar-HJ.
3-r3-Methylphenoxycarbonyl)-5-nitroρhenylboronic acid (FL-075)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous 'CH2CΪ2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with m-cresol (16 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (82% yield) of the desired compound To make compound (lm), was treated according to general procedure A, step (ii), to give 41 mg (91% yield) of the desired compound as a yellow semisolid. 1H- NMR(300MHz, 5%D2O in 6-DMSO): J2.35 [t, 3H, CH5J, 7.79-8.30 [m, 4Η, Ar-HJ, 8.71- 8.91 [m, 3Η, Ar-HJ.
3-('2,6-Dichlorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-080)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-dichlorophenol (25 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (80% yield) of the desired compound as a pale yellow powder, mp: 167-169°C. 1H-NMR(300MHz, 5%D2O in O 2005/041904
dβ-OMSO): δ739- .44 [m, IH, Ar-H], 7.52-7.67 [m, 2Η, Ar-HJ, 8.83 [s, 1Η, Ar-HJ, 8.94- 8.96 [m, 2Η, Ar-H].
3-(2-Fluorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-081)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CΗ2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-fluoroplιenol (17 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (85% yield) of the desired compound as a white needle, mp: 144-146°C. 1H-NMR (400MΗz, 5%D2O in d6-DMSO): J 7.29-7.53 [m, 4H, Ar-HJ, 8.80 [s, 1Η, Ar-HJ, 8.89-8.93 [m, 2Η, Ar-H].
3 -(2,6-Difluorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-082)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CΗ2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-difluoroρhenol (20 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (81% yield) of the desired compound as a white powder, mp: 124-126°C. 1H-NMR(400MHz, 5%D2O in d6- DMSO): J7.23-7.38 [m, 2H, Ar-H], 7.38-7.48 [m, 1Η, Ar-H], 8.81 [s, 1Η, Ar-HJ, 8.86-8.96 [m, 2Η, Ar-HJ.
3-(4-Fluorophenoxycarbonyl)-5-nitrophenylboronic acid (FL-085) O 2005/041904
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-fluoroρhenol (17 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (89% yield) of the desired compound as a white powder, mp: 233-235°C. 1H-NMR(400MHz, 5%D2O in d6-OMSO): δ 7.21-7.42 [m, 4H, Ar-HJ, 8.76 [s, 1Η, Ar-H], 8.83-8.95 [m, 2Η, Ar-HJ.
3-(2,6-Dichlorobenzyloxycarbonyl)-5-nitrophenylboronic acid (FL-086)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CmCh. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,6-dichlorobenzyl alcohol (27 mg, 0.15 mmol) according to general procedure A, step (ii), to give 49 mg (89% yield) of the desired compound as a pale yellow semisolid. 1H-NMR(400MHz, 5%D2O in <i6-
DMSO): J5.62 [s, 2H, Ar-CH2J, 7.26-7.62 [m, 3Η, Ar-H], 8.57-8.95 [m, 3Η, Ar-HJ.
3-(4-pyridyloxycarbonyl)-5-nitro-phenylboronic acid (FL-087)
O 2005/041904
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-ρyridinol (14 mg, 0.15 mmol) according to general procedure A, step (ii), to give 34 mg (79% yield) of the desired compound as a pale yellow powder, mp: 165°C(dec). 1H-NMR(400MHz, 5%D2O in dβ- DMSO): J7.43-7.50 [m, IH, Ar-H], 8.67-8.72 [m, 1Η, Ar-H], 8.77-8.86 [m, 3Η, Ar-H], 8.86- 8.97 [m, 1Η, Ar-HJ. 3-(2-Chloro-3-pyridyloxycarbonyl)-5-nitrophenylboronic acid (FL-089)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-3-ρyridinol (19 mg, 0.15 mmol) according to general procedure A, step (ii), to give 37 mg (77% yield) of the desired compound as a white powder, mp: 146-148°C. 1H-NMR(400MHz, 5%D2O in d6- DMSO): J7.57-7.63 [m, IH, Ar-HJ, 8.05-8.09 [m, 1Η, Ar-HJ, 8.39-8.43 [m, 1Η, Ar-HJ, 8.81 [s, 1Η, Ar-HJ, 8.89-8.94 [m, 2Η, Ar-HJ.
3-(2-Bromo-l-indanoxycarbonyl)-5-nitrophenylboronic acid (FL-090)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-bromo-l-indanol (32 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (71% yield) of the desired compound as a white powder, mp: 177-179°C. 1H-NMR(400MHz, 5%D2O in d6- DMSO): J3.30 [d, 2H, -CH2-], 4.26[q, 1Η, Br-CH-J, 5.44 [d, 2Η, O-CH-J, 7.20-7.32 [m, 4Η, Ar-HJ, 8.78 [s, 1Η, Ar-HJ, 8.86-8.95 [m, 2Η, Ar-HJ.
3-Phenoxycarbonyl-5-nitrophenylboronic acid (FL-092)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CΗ2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with phenol (14 mg, 0.15 mmol) according to general procedure A, step (ii), to give 39 mg (91% yield) of the desired compound as a white needle, mp: 139-141°C. IH-NMR(400MHz, 5%D2O in 6-DMSO): J 7.28-7.34 [m, 3H, Ar-HJ, 7.44-7.51 [m, 2Η, Ar-H], 8.78 [s, 1Η, Ar-HJ, 8.86-8.92 [m, 2Η, Ar- HJ.
3-(3-Nitrobenzyloxycarbonyl)-5-nitrophenylboronic acid (Compound FL-094)
In step (i) of procedure A, oxalyl chloride (35 μl, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CΗ2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-nitrobenzyl alcohol (23 mg, O 2005/041904
0.15 mmol) according to general procedure A, step (ii), to give 43 mg (82% yield) of the desired compound as a pale yellow powder, mp: 142-144°C. 'H-NMR (400MHz, 5%D2O m dβ-OMSO): J5.46 [s, 2H, Ar-CH2], 7.65-7.70 [m, 1Η, Ar-HJ, 7.93-7.97 [m, 1Η, Ar-HJ, 8.09-8.12 [m, 1Η, Ar-HJ, 8.17-8.21 [m, 1Η, Ar-HJ, 8.62-8.94 [m, 3Η, Ar-HJ.
3-(3-Chlorobenzyloxycarbonyl)-5-nitrophenylboronic acid (FL-095)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitropheήyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-chlorobenzyl alcohol (22 mg, 0.15 mmol) according to general procedure A, step (ii), to give 44 mg (88% yield) of the desired compound as a white powder, mp: 91°C(dec). 1H-NMR(400MHz, 5%D2O in d6- DMSO): J5.41 [s, 2H, Ar-CH2J, 7.41-7.61 [m, 4Η, Ar-H], 8.62-8.95 [m, 3Η, Ar-HJ.
3-(2-Bromophenoxycarbonyl)-5-nitro-phenylboronic acid (FL-096)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-bromophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 49 mg (90% yield) of the desired compound as a pale yellow powder, mp: 128-130°C. 1H-NMR(400MHz, 5%D20 in d6- DMSO): J7.26-7.35 [m, IH, Ar-HJ, 7.47-7.56 [m, 2Η, Ar-HJ, 7.76-7.81 [m, 1Η, Ar-H], 8.83- 8.94 [m, 3Η, Ar-HJ. O 2005/041904
3-(l-Benzoyl-i-Phenylmethoxycarbonyl)-5-nitrophenylboronic acid (FL-097)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with benzoin (32 mg, 0.15 mmol) according to general procedure A, step (ii), to give 43 mg (71% yield) of the desired compound as a white powder, mp: 237°C(dec). 1H-NMR(400MHz, 5%D2O in d6-OMSO): δ 7.37-7.55 [m, 3H, Ar-HJ, 7.58-7.69 [m, 3Η, Ar-HJ, 7.75-7.83 [m, 1Η, Ar-H], 7.88-7.94 [m, 1Η, Ar-H], 8.07-8.13 [m, 1Η, Ar-HJ, 8.77 [s, 1Η, Ar-HJ, 8.80-8.96 [m, 2Η, Ar-HJ.
3-(3-Boronophenoxycarbonyl)-5-nitrophenylboronic acid (Compound FL-100)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol) according to general procedure A, step (ii), to give 32 mg (64% yield) of the desired compound as a pale yellow powder, mp: 228-230°C. 'H-NMR (400MHz, 5%D2O m dβ-OMSO): J 7.30-7.36 [m, IH, Ar-HJ, 7.41-7.47 [m, 1Η, Ar-HJ, 7.60-7.63 [m, 1Η, Ar-HJ, 7.68-7.73 [m, 1Η, Ar-HJ, 8.76-8.79 [m, 1Η, Ar-HJ, 8.84-8.90 [m, 2Η, Ar-HJ. O 2005/041904
3-(3-Boronobenzyloxycarbonyl)-5-nitrophenylboronic acid (FL-101)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of ,(3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3- hydroxymethylphenylboronic acid (23 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (68% yield) of the desired compound as a yellow semisolid. lR- NMR (400MHz, 5%D2O in dβ-OMSO): J5.39 [s, 2H, Ar-CH2J, 7.27-7.84 [m, 4Η, Ar-HJ, 8.79-8.90 [m, 3Η, Ar-HJ.
4-(2-Chloro-6-nitiOphenoxycarbonyl)-3-fluorophenylboromc acid (FL-104)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CΗ2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-chloro-6-nitrophenol (26 mg, 0.15 mmol) according to general procedure A, step (ii), to give 40 mg (79% yield) of the desired compound as a pale yellow powder, mp: 174-175°C. 1H-NMR (400MHz, 5%D2O in <76-DMSO): J7.61-7.36 [m, IH, Ar-HJ, 7.71-7.74 [m, 1Η, Ar-HJ, 7.77-7.79 [m, 1Η, Ar-HJ, 8.07-8.11 [m, 2Η, Ar-HJ, 8.18-8.21 [m, 2Η, Ar-HJ. O 2005/041904
3-(2,4-Dichloro-6-nitro-phenoχycarbonyl)-5-nitro-phenylboronic acid (FL-107)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,4-dichloro-6-nitrophenol (80%) (39 mg, 0.15 mmol) according to general procedure A, step (ii), to give 52 mg (87% yield) of the desired compound as a pale yellow powder, mp: 184-186°C. 1H-NMR (400MHz, 5%D2O in^-DMSO): 8.34-8.38 [m, IH, Ar-H], 8.82-8.84 [m, 1Η, Ar-HJ, 8.90-8.91 [m, 1Η, Ar-H], 8.94-8.96 [m, 1Η, Ar-HJ.
3-("2,4-Dichloro-6-nitro-phenoxycarbonyl)-5-nitro-phenylboronic acid (FL-132)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 5-chloro-2-(2,4- dichloroρhenoxy)ρhenol (43 mg, 0.15 mmol) according to general procedure A, step (ii), to give 51 mg (71% yield) of the desired compound as a pale yellow powder, mp: 193°C. 1H- NMR (400MHz, 5%D20 in ^-DMSO): J6.61-6.94 [m, 3H, Ar-HJ, 7.15-8.07 [m, 3Η, Ar-HJ, 8.71-8.76 [m, 1Η, Ar-HJ, 8.84-8.89 [m, 1Η, Ar-H], 8.89-8.96 [m, 1Η, Ar-HJ.
3-("4-Coumarinoxycarbonyl)-5-nitrophenylboronic acid (FL-133) O 2005/041904
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 4-hydroxy coumarin (24 mg, 0.15 mmol) according to general procedure A, step (ii), to give 36 mg (67% yield) of the desired compound as a white powder, mp: 230-232°C. 1H-NMR (400MHz, 5%D2O in d6- DMSO): J7.12-7.22 [m, IH, Ar-HJ, 7.23-7.36 [m, 2Η, Ar-HJ, 7.55-7.64 [m, 1Η, Ar-HJ, 7.72- 7.86 [m, 1Η, Ar-H], 8.60 [s, 1Η, Ar-HJ, 8.72 [s, 1Η, Ar-H], 8.77 [s, 1Η, Ar-HJ.
3-(2,4.6-Trichlorophenoxycarbonyl)-5-nitro-phenylboronic acid (FL-139)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2,4,6-trichlorophenol (30 mg, 0.15 mmol) according to general procedure A, step (ii), to give 45 mg (77% yield) of the desired compound as a white powder, mp: 217°C(dec). 1H-NMR (400MHz, 5%D2O in d6- DMSO): J7.24 [s, 2H, Ar-H], 8.77-8.80 [m, 1Η, Ar-H], 8.90-8.96 [m, 2Η, Ar-HJ.
3-(l-Naphthalenemethoxycarbonyl)-5-nitrophenylboronic acid (FL-148)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1-naphthalenemethanol (24 mg, 0.15 mmol) according to general procedure A, step (ii), to give 38 mg (73% yield) of the desired compound as a pale yellow powder, mp: 230°C(dec). 1H-NMR (400MHz, 5%D O in d6-DMSO): J5.84 [s, 2H, Ar-CH2-J, 7.47-7.61 [m, 3Η, Ar-H], 7.65-7.72 [m, 1Η, Ar-H], 7.92-7.99 [m, 1Η, Ar-H], 8.02-8.16 [m, 1Η, Ar-HJ, 8.58 [s, 1Η, Ar-HJ, 8.68 [s, 1Η, Ar-H], 8.77 [s, 1Η, Ar-HJ.
3-(l , l-Diphenylmethoxycarbonyl)-5-nitrophenylboronic acid (FL-149)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CΗ2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with (40 mg, 0.15 mmol) according to general procedure A, step (ii), to give 40 mg (70% yield) of the desired compound as a pale yellow powder, mp: 217°C(dec). 1H-NMR (400MHz, 5%D2O in d6-DMSO): δ5.66 [s, 2H, Ar-CH-J, 7.13-7.18 [m, 1Η, Ar-CH-J, 7.23-7.31 [m, 3Η, Ar-HJ, 7.31-7.46 [m, 5Η, Ar-HJ, 7.48-7.54 [m, 1Η, Ar-HJ, 8.73 [s, 1Η, Ar-HJ, 8.83-8.87 [m, 2Η, Ar-HJ.
3-(2-Naphthoxycarbonyl)-5-nitrophenylboronic acid (FL-151)
In step (i) of procedure A, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of, DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 2-naphthol (22 mg, 0.15 mmol) according to general procedure A, step (ii), to give 41 mg (82% yield) of the desired compound as a pale yellow powder, mp: 256°C(dec). 1H-NMR (400MHz, 5%D2O in d(,- DMSO): J7.42-7.54 [m, 3H, Ar-HJ, 7.78-8.02 [m, 4Η, Ar-HJ, 8.74-8.79 [m, 1Η, Ar-HJ, 8.80- 8.86 [m, 1Η, Ar-H], 8.86-8.91 [m, 1Η, Ar-HJ.
3-(3-Boronobenzyloxycarbonyl)-5-nitrophenylboronic acid (Compound FL-171)
In step (i) of procedure A, oxalyl chloride (35 μl, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Q2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 3- hydroxymethylphenylboronic acid (23 mg, 0.15 mmol) according to general procedure A, step (ii), to give 35 mg (68% yield) of the desired compound as a yellow semisolid. *H- NMR (400MHz, 5%D2O in dβ-DMSO): J5.39 [s, 2H, Ar-CH2], 7.27-7.84 [m, 4Η, Ar-H], 8.79-8.90 [m, 3Η, Ar-HJ.
1.2 General Procedure B: Synthesis of boronobenzoic acid phenylene esters If"*' !_,-■ '! ■>'* 'U' •■ •>' "■"" '' '' ' "'' "'"'' '""
i, (COCl)2, DMF, CH2C12, rt, overnight ii, Et3N, THF, rt, overnight
In step (i), oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of compound B-l (0.2 mmol), 1 drop of DMF and 5 mL of dried CH2CI2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride B-2 as a solid, which was used without further purification in step (ii). In step (ii), a suspension of the acid chloride B-2 (0.2 mmol, obtained from step (i) above) in 5 mL of dried THF was added dropwise to an ice-cold solution of B-3 (0.075 mmol), anhydrous triethyl amine (42 μL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10). The product yielded from step (ii) is B-4.
3-Borono-5-nitrobenzoic acid 1,4-phenylene ester (FL-078)
ll '' if„i' 'I .•' ,V •«"!' 't-"1' !l '' " ''' "'"'' """ " '""
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with hydroquinone (9 mg, 0.075 mmol) according to general procedure B, step (ii), to give 32 mg (86% yield) of the desired compound as a white powder, mp: 271-273°C. 1H-NMR(300MHz, 5%D2O in β-DMSO): J 7.43 [s, 4H, Ar-H], 8.79 [s, 2Η, Ar-HJ, 8.84 [s, 2Η, Ar-H], 8.86 [s, 2Η, Ar-HJ.
3-Borono-5-nitrobenzoic acid 2-chloro-l,4-phenylene ester (FL-079)
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with chlorohydroquinone (11 mg, 0.075 mmol) according to general procedure B, step (ii), to give 31 mg (78% yield) of the desired compound as a white powder, mp: 264-266°C. 1H-NMR(300MHz, 5%D2O in dβ- DMSO): δl.46-7.79 [m, 3H, Ar-HJ, 8.79 [d, 1Η, Ar-H], 8.88-8.92 [m, 2Η, Ar-HJ.
4-Borono-2-fluorobenzoic acid 2-chloro-l,4-phenylene ester (FL- 103)
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with and chlorohydroquinone (11 mg, 0.075 mmol) according to general procedure B, step (ii), to give 26 mg (74% yield) of the desired compound as a pale yellow powder, mp: 228-230°C. 'H-NMR (400MHz, 5%D2O in dβ-OMSO): J6.52-6.55 [m, IH, Ar-H], 6.68-6.76 [m, 2Η, Ar-H], 6.94-7.06 [m, 1Η, Ar-HJ, 7.21-7.34 [m, 1Η, Ar-H], 7.57-7.78 [m, 3Η, Ar-HJ, 7.99-8.11 [m, 1Η, Ar-HJ.
3-Borono-5-nitrobenzoic acid 1,3-phenylene ester (FL- 106)
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with resorcinol (9 mg, 0.075 mmol) according to general procedure B, step (ii), to give 26 mg (70% yield) of the desired compound as a pale yellow powder, mp: 134°C(dec). 'H-NMR (400MHz, 5%D2O in d&- DMSO): J6.14-6.18 [m, 2H, Ar-HJ, 7.33-7.45 [m, 2Η, Ar-H], 8.75-8.82 [m, 2Η, Ar-H], 8.85-8.90 [m, 4Η, Ar-HJ.
3-Borono-5-nitrobenzoic acid 1,2-benzenedimethanol ester (FL- 136)
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1,2-benzenedimethanol (10 mg, 0.075 mmol) according to general procedure B, step (ii), to give 21 mg (53% yield) of the desired compound as a pale yellow powder, mp: 142°C(dec). lH-NMR (400MHz, 5%D2O in dβ-OMSO): J 5.64 [s, 4H, CH2], 6.14-6.18 [m, 2H, Ar-HJ, 7.33-7.45 [m, 4Η, Ar-HJ, 8.77-8.84 [m, 2Η, Ar-HJ, 8.87-8.93 [m, 4Η, Ar-HJ.
3-Borono-5-nitrobenzoic acid 2,3,5,6-tetrachloro-l,4-phenylene ester (FL-141)
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted tetrachlorohydroquinone (19 mg, 0.075 mmol) according to general procedure B, step (ii), to give 33 mg (69% yield) of the desired compound as a white powder, mp: 252°C. 1H-NMR(300MHz, 5%D2O in dβ- OMSO): 8.71-8.75 [m, 2H, Ar-HJ, 8.93-8.99 [m, 4Η, Ar-HJ.
3-Borono-5-nitrobenzoic acid, 1,4-dihydroxynaphthalene ester (FL-167)
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with 1,4-naphthalenediol (12 mg, 0.075 mmol) according to general procedure B, step (ii), to give 24 mg (59% yield) of the desired compound as a pale yellow powder, mp: 270°C(dec). 1H-NMR(300MHz, 5%D2O in dβ-OMSO): J 6.89 [s, 2H, Ar-HJ, 7.68-7.74 [m, 2Η, Ar-HJ, 8.08-8.13 [m, 2Η, Ar-HJ, 8.70 [s, 2Η, Ar-HJ, 8.85 [s, 2Η, Ar-HJ, 8.93 [s, 2Η, Ar-HJ.
3-Borono-5-nitrobenzoic acid, 2-tert-butyl-l,4-phenylene ester (FL-169)
In step (i) of procedure B, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with tert-butylhydroquinone (12 mg, 0.075 mmol) according to general procedure B, step (ii), to give 22 mg (43 % yield) of the desired compound as a brown powder, mp: 268°C(dec). 1H-NMR(300MHz, 5%D2O in dβ-OMSO): δ 1.37 [s, 9H, -CH3J, 7.10-7.13 [m, IH, Ar-H], 7.27-7.31 [m, 1Η, Ar-HJ, 7.51-7.54 [m, 1Η, Ar-HJ, 8.65 [s, 2Η, Ar-H], 8.77 [s, 2Η, Ar-H], 8.88 [s, 2Η, Ar-HJ. O 2005/041904
1.3 General procedure C: synthesis of acyloxyphenylboronic acids
C-l
C-2 To an ice-cold solution of C-l (0.15 mmol), dried triethyl amine (28 μL, 0.2 mmol) and 10 mL of dried THF was added dropwise a solution of C-2 (0.1 mmol) in 5 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10). The product yielded is C-3.
1,4-Benzenedicarboxylic acid, di 3-boronophenyl ester (Compound FL-156)
3-Hydroxyphenylboronic acid (21 mg, 0.15 mmol) and terephthaloyl chloride (21mg, 0.1 mmol) were reacted according to general procedure C, to give 16 mg (51 % yield) of the desired compound as a white powder, mp: 214°C(dec). !H-NMR (400MHz, 5 D2θ in dβ- OMSO): J7.28-7.34 [m, 2H, Ar-HJ, 7.38-7.46 [m, 2Η, Ar-HJ, 7.59-7.63 [m, 2Η, Ar-HJ, 7.68-7.73 [m, 2Η, Ar-HJ, 8.30 [s, 4Η, Ar-HJ. 1.4 General Procedure D: Synthesis of amide of boronoanilines
To an ice-cold solution of D-l (0.5 mmol) and NaHCOs (105 mg, 1.25 mmol) in 10 mL of water and 10 mL of ether was add dropwise D-2 (0.5 mmol) over a period of 30 min. The reaction mixture was kept at 0°C for lh and then stirred at room temperature overnight. It was then extracted twice with 10 mL of ethyl ether. The aqueous solution was acidified with IN aqueous HCI and extracted twice with 10 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine solution, dried (Na2SO4) and concentrated. The residue was recrystallized from ethyl acetate/hexane. The product yielded is D-3.
3-(2-Fluorobenzamido)-5-carboxylphenylboronic acid (Compound FL-083)
2-Fluorobenzoyl chloride (60μL, 0.5 mmol) and 3-amino-5-carboxylphenylboronic acid (91 mg, 0.5 mmol) were reacted according to general procedure D, to give 94 mg (62% yield) of the desired compound as a white powder, mp: 224-225°C. lH-NMR(300MHz, 5%D2O in dβ-OMSO): 7.21-7.38 [m, 2H, Ar-HJ, 7.48-7.72 [m, 2Η, Ar-H], 8.12-8.33 [m, 3Η, Ar- HJ. 3-(2-Fluorobenzamido)-5-nitrophenylboronic acid (FL-084)
2-Fluorobenzoyl chloride (60μL, 0.5 mmol) and 3-amino-5-nitrophenylboronic acid hydrochloride (109 mg, 0.5 mmol) were reacted according to general procedure D, to give 82 mg (54% yield) of the desired compound as a white powder, mp: 212-214°C. *H- NMR(300MHz, 5%D2O in dβ-OMSO): J7.22-7.42 [m, 2H, Ar-HJ, 7.53-7.63 [m, 1Η, Ar- HJ, 7.64-7.72 [m, 1Η, Ar-HJ, 8.34 [s, 1Η, Ar-HJ, 8.37 [s, 1Η, Ar-HJ, 8.79 [s, 1Η, Ar-HJ.
3-(2,6-Dichlorobenzamido)-5-nitrophenylboronic acid (FL-108)
2,6-Dichlorobenzoyl chloride (72μL, 0.5 mmol) and 3-amino-5-carboxylphenylboronic acid hydrochloride (109 mg, 0.5 mmol) were reacted according to general procedure D, to give 113 mg (64% yield) of the desired compound as a white powder, mp: 267°C(dec). *Η- NMR(300MHz, 5%D2O in dβ-OMSO): J7.46-7.53 [m, IH, Ar-HJ, 7.54-7.60 [m, 2Η, Ar- HJ, 8.27 [s, 1Η, Ar-HJ, 8.40 [s, 1Η, Ar-HJ, 8.74 [s, 1Η, Ar-HJ.
3-(2,6-Dichlorobenzamido)-4-chlorophenylboronic acid (FL-109)
2,6-Dichlorobenzoyl chloride (72μL, 0.5 mmol) and 3-amino-4-chlorophenylboronic acid hydrochloride (104 mg, 0.5 mmol) were reacted according to general procedure D, to give 98 mg (57% yield) of the desired compound as a pale yellow powder, mp: 246°C(dec). 'H- NMR(300MHz, 5%D2O in J 7.41-7.57 [m, 4H, Ar-HJ, 7.62-7.68 [m, 1Η, Ar- H], 7.95-8.01 [m, 1Η, Ar-HJ.
3-(2,6-Dichlorobenzamido)-4-methylphenylboronic acid (FL-110)
2,6-Dichlorobenzoyl chloride (72μL, 0.5 mmol) and 3-amino-4-methylphenylboronic acid hydrochloride (94 mg, 0.5 mmol) were reacted according to general procedure D, to give 79 mg (49% yield) of the desired compound as a white powder, mp: 234-236°C. *H- NMR(300MHz, 5%D2O in J 2.26 [s,3H,-CH3], 7.15-7.25 [m, 1Η, Ar-HJ, 7.40-7.47 [m, 1Η, Ar-H], 7.47-7.60 [m, 3Η, Ar-H], 7.71-7.77 [m, 1Η, Ar-HJ.
3-Benzamido-5-nitrophenylboronic acid (FL-113)
Benzoyl chloride (58μL, 0.5 mmol) and 3-amino-5-nitrophenylboronic acid hydrochloride (109 mg, 0.5 mmol) were reacted according to general procedure D, to give 94 mg (66% yield) of the desired compound as a pale yellow powder, mp: 227-229°C. 'Η- NMR(300MΗz, 5%D2O in dβ-OMSO): J7.49-7.54 [m, 2H, Ar-H], 7.56-7.61 [m, 1Η, Ar- HJ, 7.94-7.99 [m, 2Η, Ar-HJ, 8.36 [s, 1Η, Ar-HJ, 8.46 [s, 1Η, Ar-H], 8.84 [s, 1Η, Ar-Hj. 1.5 General Procedure E: Synthesis of boronobenzoic acid phenylene amides
In step (i), oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of compound E-1 (0.2 mmol), 1 drop of DMF and 5 mL of dried CH2CI2. The reaction mixture was stiπed at room temperature overnight and then evaporated to dryness to afford acid chloride E-2 as a solid, which was used without further purification in step (ii). In step (ii), a suspension of the acid chloride E-2 (0.2 mmol, obtained from step (i) above) in 5 mL of dried THF was added dropwise to an ice-cold solution of E-3 (0.075 mmol), anhydrous triethylamine (42 μL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ether and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was recrystallized from ethyl acetate/hexane. The product yielded from step (ii) is E-4.
3-Borono-5-nitrobenzoyl-l ,4-phenylenediamine (FL-166)
In step (i) of procedure E, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2CI2. The reaction was stirred overnight at room temperature and then evaporated to dryness. The product obtained was reacted with J-phenylenediamine (8 mg, 0.075 mmol) according to general procedure E, step (ii), to give 29 mg (78% yield) of the desired compound as pale yellow powder, mp: 254-256°C. 1H-NMR(300MHz, 5%D2O in dβ-OMSO): J7.73 [s, 4H, Ar-H], 8.67-8.70 [m, 2Η, Ar-HJ, 8.72-8.78 [m, 4Η, Ar-HJ. 1.6 Additional Synthetic Examples
3-amino-5-carboxylphenylboronic acid (FL-088)
To make desired compound, a solution Of 3-carboxyl-5-nitrophenylboronic acid (422 mg, 2 mmol) in absolute ethanol (5 ml) was hydrogenated in the presence of Raney Nickel (150 mg) for 6 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness, then the residue was reerystallized from water to give 257 mg (71% yield) of the desired compound as a pale yellow powder, mp: 210-212°C (Ref. mp: 212-214°C). Η- NMR(400MHz, 5%D2O in d6-OMSO): J7.06 [s, IH, Ar-HJ, 7.16 [s, 1Η, Ar-HJ, 7.55 [s, 1Η, Ar-H] (Torssell, K.; Meyer, Η.; Zacharias, B. Arlάv Kemi 1957, 10, 497-505).
3-(2, 6-dichlorophenylcarbonyloxy)phenyl boronic acid (FL-099)
To make desired compound, a solution of 2,6-dichlorobenzoyl chloride (29 μL, 0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethylamine (42 μL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO ) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 38 mg (81% yield) of desired compound as a white powder, mp: 238°C(dec). 1H-NMR (400MHz, 5%D2O in 6-DMSO): J7.08-7.19 [m, IH, Ar-HJ, 7.22-7.30 [m, 1Η, Ar-H], 7.22- 7.30 [m, 1Η, Ar-H], 7.42-7.50 [m, 1Η, Ar-H], 7.54-7.60 [m, 1Η, Ar-H], 7.60-7.68 [m, 2Η, Ar- HJ, 7.73-7.78 [m, 3Η, Ar-H].
3-benzenesulfonamido-5-nitrophenylboronic acid (FL-114)
To make desired compound, a solution of benzenesulfonyl chloride (19 μL, 0.15 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-amino-5- nitrophenylboronic acid, HCI (33 mg, 0.15 mmol), dried triethylamine (63 μL, 0.45 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ether and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 37 mg (77% yield) of desired compound as a white powder, mp: 238°C(dec). 1H-NMR (400MHz, 5%D2O in d6-DMSO): J7.49-7.61 [m, 3H, Ar-H], 7.72-7.78 [m, 2Η, Ar-HJ, 7.82- 7.85 [m, 1Η, Ar-H], 7.93-7.96 [m, 1Η, Ar-H], 8.25-8.29 [m, 1Η, Ar-HJ.
Tris-(3-borono-5-nitrobenzoic acid), 1,3,5-trihydroxybenzene ester (FL-164
In step (i), oxalyl chloride (79 μL, 0.9 mmol) was added to a suspension of (3τcarboxyl-5- nitrophenyl)boronic acid (95 mg, 0.45 mmol), 1 drop of DMF and 10 mL of dried CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii). In step (ii), a suspension of the above acid chloride (0.45 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of phloroglucinol (13 mg, 0.1 mmol), anhydrous triethylamine (63 μL, 0.45 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 17 mg (24% yield) of the desiredcompound as a pale yellow powder, mp: 274°C(dec). 1H- NMR (400MHz, 5%D2O in d6-OMSO): J7.46 [s, IH, Ar-HJ, 8.72-8.76 [m, 1Η, Ar-HJ, 8.78- 8.86 [m, 2Η, Ar-H].
Tris(3-borono-5-nitrobenzoic acid), triethanolamine ester (FL-165)
In step (i), oxalyl chloride (79 μL, 0.9 mmol) was added to a suspension of (3-carboxyl-5- nitrophenyl)boronic acid (95 mg, 0.45 mmol), 1 drop of DMF and 10 mL of dried CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii). In step (ii), a suspension of the above acid chloride (0.45 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of triethanolamine (15 mg, 0.1 mmol), anhydrous triethylamine (42 μL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with water, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 14 mg (19% yield) of the desired compound as a pale yellow powder, mp: 235°C(dec). 1H-NMR (400MHz, 5%D2O in 6-DMSO): J2.05 [t, 3H, -CH2-J, 4.05 [t, 2Η,-CH2-J, 8.59-8.63 [m, 3Η, Ar-H], 8.71-8.76 [m, 3Η, Ar-H], 8.77-8.81 [m, 3Η, Ar-HJ.
3-borono-5-nitrobenzoyl-L-phenylalanine ethyl ester (FL-170)
In step (i), oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5- nitrophenyl)boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 10 mL of dried CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii). In step (ii), a solution of the above acid chloride (0.2 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to an ice-cold solution of L-phenylalanine ethyl ester hydrochloride (34 mg, 0.15 mmol), anhydrous triethylamine (63 μL, 0.45 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCI, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO ) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 31 mg (54% yield) of the desired compound as a pale yellow powder, mp: 264°C(dec). 1H-NMR (400MHz, 5%D2O in 6-DMSO): J1.35 [t, 2H,- CH2CH3J, 3.13 [dd, 1Η, -CH2-J, 4.02 [q, 2Η, -CH2CH3J, 4.71 [m, IH, -CH-], 7.05-7.37 [m, 5H, Ar-H], 8.57-8.63 [m, 1Η, Ar-H], 8.67-8.72 [m, 2Η, Ar-H], 8.73-8.80 [m, 1Η, Ar-HJ. "
3-(3-boronobenzyloxycarbonyl)-5-aminophenylboronic acid (FL-171) Η
To make the desired compound, a solution of 3-(3-boronobenzyloxycarbonyl) •
5-nitrophenylboronic acid (172 mg, 0.5 mmol) in absolute ethanol (10 ml) was hydrogenated in the presence of Raney Nickel (80 mg) for 4 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness, then the residue was recrystallized from ethanol/H2O to give 60 mg (38% yield) of the desired compound as a pale yellow semisolid.
1H-NMR(300MHz, 5%D2O in d6-OMSO): J5.25 [s, 2H, Ar-CH2], 6.56-6.97 [m, 2Η, Ar-H],
7.15-8.09 [m, 5Η, Ar-HJ. (3-carboxy-5-hydroxyphenyl)boronic acid (FL-172)
To make the desired compound, 3-amino-5-carboxylphenylboronic acid hydrochloride (22 mg, 0.1 mmol) was suspended in 2 mL of 50% H2SO4 and treated at -5 °C with a solution of NaNO2 (8 mg, 0.1 mmol) in 1 mL of water. After the mixture had been stirred for 1 h at this temperature, water (10 mL) was added and the mixture was warmed to 60 °C until the evolution of gas ceased. The dark brown solution was extracted twice with ether, and the extracts were washed with water and brine and dried with Na2SO . The solvent was evaporated to dryness, then the residue was recrystallized from methanol to give 5 mg (27% yield) of the desired compound as a pale yellow powder, mp: 229°C(dec). 1H- NMR(300MHz, 5%D2O in d6-DMSO): J7.19-7.41 [m, 2H, Ar-H], 7.77-7.87 [m, 1Η, Ar-HJ.
3-Benzyloxycarbonyl-5-nitrophenylboronic acid (Compound FL-1201)
FL-1201 is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2188).
3-(Benzylcarbamoyl)phenylboronic acid (Compound FL-1010)
FL-1010 is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-3055). EXAMPLE 2 Cloning of Recombinant SARS-Associated 3CLpro Protease cDNA corresponding to the SARS 3CL protease gene (Tor2 strain, GenBank #AY274119) inserted in a pBR194c vector was kindly provided by British Columbia Cancer Agency Branch (Vancouver, British Columbia, Canada). Competent cells (XL-1 Blue, Stratagene) were transformed for plasmid propagation under ampicillin selection. DNA plasmid was isolated (Plasmid Midi Kit, Qiagen) and the gene was amplified by PCR with appropriate primers using Pfu Turbo DNA Polymerase (Stratagene). To prevent artifacts afterward, the original plasmid was degraded by Dpnl (Stratagene) digestion reaction (1 hour at 37°C) followed by inactivation of Dpnl (20 minutes at 80°C). Cloning reaction was performed by blunt-end directional cloning (Champion pET Directional TOPO Expression and Cloning Kit, Invitrogen) by topo-isomerase reaction in a pETlOO vector, where the protein expression is chemically induced and under the control of the T7 promoter. The protease gene was cloned in frame with an N-terminal peptide containing a poly-histidine tag for further purification by affinity chromatography. An enterokinase recognition site was present to remove the amino terminal tag after purification. One Shot TOP 10 competent cells (Invitrogen) were transformed with the product from the cloning reaction. DNA plasmid was purified and the gene insertion and its directionality, as well as the integrity of pETlOO vector were confirmed by DNA sequencing. BL21 Star DE3 (Invitrogen) competent cells were transformed for protein expression under ampicillin selection and IPTG induction.
EXAMPLE 3 Expression and Purification of Recombinant SARS-Associated 3CLpro Protease Plasmid-encoded SARS 3CL protease was expressed as a soluble fraction in BL21
Star DE3 Escherichia coli competent cells (Invitrogen). Cells were grown in LB supplemented with ampicillin (50 μg/ml) at 37°C, induced with IPTG when the optical density was ~ 0.8 and harvested after 3 - 4 hours. Cells were re-suspended in lysis buffer (potassium phosphate 50 mM, pH 7.8, sodium chloride 400 mM, potassium chloride 100 mM, glycerol 10%, triton-X 0.5%, imidazole 10 mM) and broken with three passes through a French pressure cell (> 16,000 psi). Cell debris was collected by centrifugation (20,000g at 4°C for 20 min.). The supernatant was diluted 1:3 with binding buffer (sodium phosphate 50 mM, pH 7.5, sodium chloride 0.3 M, imidazole 10 mM), filtered using a 0.22 m pore size filter (Millipore) and applied directly to a nickel-affinity column (HisSelect, Sigma) which had been pre-equilibrated with five column volumes of the binding buffer. The protease was eluted with a linear gradient of elution buffer (sodium phosphate 50 mM, pH 7.5, sodium chloride 0.3 M, imidazole 250 mM) at fractions corresponding to 0 - 30% elution buffer. Protease fractions were pooled and concentrated. During concentration the elution buffer was exchanged gradually for storage buffer (sodium phosphate 10 mM, pH 7.4, sodium chloride 10 mM, DTT 1 mM, EDTA 0.5 mM). The poly-histidine tag of the fusion protein was cut through incubation with 0.1 units of enterokinase (Invitrogen) for 48 hours at 4°C. Efficiency of the cleavage reaction was inspected by SDS PAGE. This reaction mixture was passed again through the nickel-affinity column and the flow-through containing the protease was collected. The sample was diluted 4-fold with storage buffer and then concentrated (> 10 mg/ml). The purified protein was then stored at -20°C. Purity of the sample was higher than 95% , assessed by SDS PAGE.
EXAMPLE 4. Enzymatic Characterization of Recombinant SARS-Associated 3CLpro Protease The activity of the SARS protease was determined by continuous kinetic assays using the fluorogenic substrate Dabcyl-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Arg-Edans (Bachem). The hydrolysis of the substrate is accompanied by a proportional increase of the fluorescence intensity of the Edans group due to a decreased FRET efficiency following the release of the Dabcyl-linked peptide quencher fragment. The fluorescent intensity was monitored in a Cary Eclipse fluorescence spectrophotometer (Varian) using wavelengths of 360 nm and 500 nm for the excitation and emission, respectively. The experiments were performed with the same buffer used to store the enzyme (sodium phosphate lOmM, pH 7.4, sodium chloride lOmM, DTT lmM, EDTA 0.5 mM). To determine the kinetic parameters, Km and feat, initial rate measurements were performed by incubating the enzyme with the substrate at room temperature. In a microcuvette with a final volume of 120 μL, the reaction was initiated by adding the protease (final concentration 1 μM) to a solution of substrate at final concentration of 0 - 120 μM.
EXAMPLE 5. Inhibition Kinetics of Recombinant SARS-Associated 3CLpro protease
Inhibition assays were performed under the same conditions at increasing concentration of inhibitor. Protease (final concentration 1 μM) was incubated for 20 minutes at room temperature with the inhibitor (final concentration 0 - 150 μM) and the reaction was initiated adding substrate to a final concentration of 5 μM. Inhibition constants, i, were obtained as adjustable parameters through non-linear square fitting of the initial enzymatic rates as a function of the inhibitor concentration according to the following equation: v, _ t [I]τ +[E]T +K{ - ([IJT +[E]T +Kt. -4[I]T[EJT v0 2[EJT
where vi and vo are the initial rate at a given inhibitor concentration and at zero inhibitor concentration, respectively, [IJτ is the total inhibitor concentration and [EJT is the total enzyme concentration. The reversibility of the inhibition was confirmed by dilution experiments. Table 16 shows the results obtained for nine different members of the family of
SARS-associated coronavirus protease 3CLpro inhibitors described in this disclosure. Table 16. Inhibition of SARS Associated Coronavirus Protease 3CLpro by Boronic Acids
EXAMPLE 6 Binding Energetics of Inhibitors The binding of the various boronic acids of the present invention to the SARS- associated coronavirus protease 3CLpro was measured by isothermal titration calorimetry and the results are set forth in Table 17 below. Isothermal titration calorimetry does not only measure the binding affinity of inhibitors but also dissects the enthalpic and entropic components to binding, thus allowing identification of the forces involved in the association reaction. In general a binding reaction characterized by a favorable enthalpy change indicates that the inhibitor establishes strong interactions with the target, whereas an inhibitor characterized by unfavorable binding enthalpy is driven by non-specific hydrophobic interactions, i.e. a tendency to escape water rather than a strong attraction to the target (Velazquez-Campoy et al, 2001; Luque and Freire, 2002; Ohtaka et al, 2002).
Table 17. Binding Enthalpy of Selected Compounds to 3CLpro
The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Numerous references, including patents, patent applications, protocols and various publications, are cited and discussed in the description of this invention. The citation and/or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is "prior art" to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entirety and to the same extent as if each reference was individually incorporated by reference.

Claims

WHAT IS CLAIMED IS: 1. A compound described by formula (1):
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein R14 and R15 are each independently hydrogen, CM alkyl or benzyl), Ri4Ri5RiδN+G" (wherein Ru, R15 and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, - SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH=CH-,
-NH-Cm-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CH.)i or -(CH=CH)j(wherein i = 0, 1, 2, or 3 and j = 0 or 1), - CHR9- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and R15 are each independently hydrogen or CM alkyl), Ri4Ri5RiδN+G" (wherein R14, R15 and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -
-CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9θH(whereϊn R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), R14R15N- (wherein Rw and R15 are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, R14R15N- (wherein Ru and R15 are each independently hydrogen or CM alkyl), Ri4Ri5RieN+G" (wherein R14, R15 and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH,
-C(Cm)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-δ alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and the heterocyclic alkene means a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, (1) when Ri through R4 are H, X is not a -NH-CH2- or -CH2-NH-; (2) when Ri = R2 = H, X is not -CO-NH-; (3) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-; (4) when X =-CO-O-, Y = -O-CO-, m=0, n = 0 and U is a 1,4-benzene, a 1,4-benzocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13; (5) when Ri through Rsare H, X = -CO-O-, m=n=l, U = 1,4-benzene, Y=- O-CO-, Q is not 4-boronophenyl; (6) when Ri through Rsare H, X = -CO-O-, m=n=l, U = 1,3-benzene, Y=- O-CO-, Q is not 4-boronophenyl; (7) when Rt through Rs are H, X = -CO-O-, m=n= 1, U = 1,2-benzene, Y=- O-CO-, Q is not 4-boronophenyl; (8) when Rt through Rtare H, X = -NH-SO2-, m=n=0, U = 4-methoxy- 1,3- benzene, Y=-N=N-, Q is not 4-(dimethylamino)-l-naphthalenyl; and (9) when Ri is amino, R2 through Rtare H, X=Y = -N=N-, m=n=0, U is 1,4- naphthalene, Q is not 3-boronophenyl.
2. A compound described by formula (2): wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, R14R15N- (wherein R14 and R15 are each independently hydrogen, CM alkyl or benzyl), Ri4Ri5RiδN+G" (wherein R14, R15 and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(Cm)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH=CH-,
-NH-Cm-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(CBb), or -(CH=CH)j(wherein i = 0, 1, 2, or 3 and j = 0 or 1), - CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic - alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10J, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein R14 and R15 are each independently hydrogen or CM alkyl), Ri4Ri5RiδN+G" (wherein R14, R15 and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -
-CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CmCHRuCORi2θr -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and R15 are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Ri4 and R15 are each independently hydrogen or CM alkyl), Rι4Ri5RiδN+G" (wherein Rw, R15 and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH,
-C(Cm)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR>oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and the heterocyclic alkene means a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, (1) when Ri through Rt represent hydrogen, X is not -NH-CO-, -NH-SO2-, -NH- (2) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-; (3) when X =-CO-O-, Y = -O-CO-, m=0, n = 0 and U is a 1,3-benzene, 1,4- benzene, a 1,3-benzocyclic alkene, a 1,4-benzocyclic alkene, a 1,3-benzoheterocyclic alkene or a 1,4-benzoheterocyclic alkene, Q is not 4-boronophenyl, which may be substituted with one or more substituents R13; (4) when Rt is borono, Ri through R3 and R> through Rs are H, X = -CO-NH-, Y=
-CO-O-, m=n= l, U = -CH2-CH2-CH2-, Q is not 2,5-dioxo-l-pyrrolidinyl; and (5) when R3 is borono, Ri. R2 and R5 through Rs are H, X = -CO-NH-, Y=-CO- O-, m=n= l, U = -CH2-CH2-CH2-, Q is not 2,5-dioxo-l-pyπolidinyl;
3. A compound described by formula (3):
wherein Ri through R* each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, R14R15N- (wherein R14 and R15 are each independently hydrogen, CM alkyl or benzyl), Ri4Ri5RtδN+G~ (wherein R14, R15 and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBFi), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ct-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -C(Cm)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, -SO2Cm, -SO2NH2; R5 through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH=CH-,
-NH-Cm-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH- or -NH-SO2-; U represents-(Cm)i or -(CH=CH)j(wherein i - 0, 1, 2 or 3 and j = 0 or 1), - CHRs- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rι and R15 are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, R15 and Rtβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H, -SO∑Cm, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents TCH2CHR11COR12 or -CHRuCORn [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are .each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRtsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO- or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, (1) when Ri through Rtare H, X is not -CH2-NH-, and (2) when Q is 3-boronophenyl, Y is not -CO-NH or -SO2-NH-.
4. A compound described by formula (4):
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RuRisRi6N+G~ (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(Cm)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - R> and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH-CO-, -CH=N-, -CH=CH-, -NH-Cm-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CmCHRuCORπor -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Ri3, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G~ (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, (1) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (2) when Ri through Rtare H, m=n=0, X is not -CO-O-; (3) when Rt = R2 = H, X is not -CO-NH-; (4) when X =-CO-O-, Rs = H, Re = H, m= 1 and n = 0, Q is not a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13; (5) when X =-CO-O-, m=0 and n = 0, Q is not a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substirated with one or more substituents R13; (6) when Ri through Rt are H, X = -CO-O- and m=n=0, Q is not 2,5-dioxo-l- pyrrolidinyl; (7) when Ri through R4are H, X = -CO-O- and m=n=0, Q is not cyclohexyl; (8) when Ri through Rt are H, X = -O-CO- and m=n=0, Q is not cyclopropyl; (9) when Ri through Rtare H, X = -NH-SO2-, m=n=0, Q is not 4-(4,5- dihydro-3-phenyl- 1 H-pyrazol- 1 -yl)phenyl ; (10) when Ri through Rtare H, X = -NH-SO2-, m=n=0, Q is not 5- (dimethy lamino)- 1 -naphthaleny 1 ; (11) when Ri through Rtare H, X =-NH-Cm- and m=n=0, Q is not phenyl; (12) when Ri through R4are H, X = -NH-CO-, m=n=0, Q is not phenyl; (13) when Ri through Rtare H, X = -NH-CO- and m=n=0, Q is not phenyl; (14) when Ri through R4are H, X = -NH-CO- , m=n=0, Q is not 4-chloro-3-(4- methyl- 1 -piperazinyl)pheny 1 ; (15) when Ri through Rtare H, X = -NH-CO-, m=n=0, Q is not 4-methoxy-3- (4-methyl-l-piperazinyl)phenyl; (16) when Ri through Rtare H, X = -NH-CO-, m=n=0, Q is not 3-methoxy-4- (4-methyl- 1 -piperazinyl)phenyl ; (17) when Ri, Rs through Re are H, R2 is methoxyl, X = -NH-CO-, m=2, n=0, Q is not phenyl; (18) when Ri through Rtare H, X = -N=N-, m=n=0, Q is not 4- (dimethylamino)pheny 1 ; (19) when Ri is amino, R> through R4 are H, X = -N=N-, m=n=0, Q is not 1- naphthalenyl; (20) when Ri is amino, R2 through Rt are H, X = -N=N-, m=n=0, Q is not 4- carboxyphenyl; and (21) when Ri through R4are H, X = -N=N-, m=n=0, Q is not 2-hydroxy-l- naphthalenyl).
5. A compound described by formula (5): wherein
Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CONHOH, -SOsH, -SO2CH3, or
Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, , hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH- CO-, -CH=N-, -NH-Cm-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-or -NH-SO2-; Q represents -CmCHRuCORi2 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRtsRi6N+G~ (wherein Rw,Rιs and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein Rι9 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, (1) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (2) when R2 and Rs are H, m=n=0, X is not -CH=CH-; (3) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -CO-O-; (4) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -NH-CO-; (5) when m=0, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -O-CO-; (6) when Rs and Rβ = H, m=l, n = 0 and Q is a benzene, a benzocyclic alkene or a benzoheterocyclic alkene, which may be substituted with one or more substituents R13, X is not -CO-O-; (7) when Ri through Rtare H, X = -CO-NH-, m=n=0, Q is not phenyl; (8) when Ri and R2 are H, Rs is F, Rt is methyl, X = -CO-NH-, m=n=0, Q is not cyclopropyl; (9) when Ri through Rβare H, X = -CO-NH-, m=3, n=0, Q is not phenyl; (10) when Ri through Re are H, X = -CH2-CH-, m= 1, n=0, Q is not phenyl; (11) when Ri through Rtare H, X = -NH-CH2-, m=0 and n=l, Q is not phenyl; (12) when Ri through Rt are H, X = -NH-CH2-, m=0 and n=0, Q is not pentafluorophenyl ; (13) when Ri through Rt are H, X = -CH=CH-, m=0 and n=0, Q is not phenyl; and (14) when Ri through Rt are H, X = -CH=CH-, m=0 and n=0, Q is not 2- boronophenyl.
A compound described by formula (6): wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CHs)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, - Rs and Rδ each independently represents hydrogen, CM alkyl, JC3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0 or 1; X is -CO-O-, -CH=CH-CO-O-, -O-CO-, -CO-NH-, -CH=CH-CO-NH-, -NH-CO-, -CH=N-, -CH=CH-, -NH-Cm-, -CH2-NH-, -CH2-O-, -SO2-O-, -O-SO2-, -SO2-NH-, or
Q represents -CmCHRuCORπor -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRt9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, (1) when Ri through Rt are H, X is not -CH2-NH-; (2) when m = 0 and Q is 3-boronophenyl, X is not -CO-NH or -SO2-NH-; (3) when Ri through Rt are H, X = -NH-CO-, m=0 and n= 1, Q is not phenyl; (4) when Ri through Rtare H, X = -NH-CO-, m=0 and n=0, Q is hot phenyl; (5) when Rt through Rtare H, X = -NH-CH2-, m=0 and n=l, Q is not phenyl; (6) when Ri through Re are H, X = -NH-CH2-, m=2 and n=l, Q is not phenyl; (7) when Ri through Rt are H, X = -NH-CH2-, m=0 and n= 1, Q is not 10- (hydroxymethyl)-9-anthracenyl; (8) when Ri through Rt are H, X = - NH-CH2-, m=n=0, Q is not phenyl; (9) when Ri through Rsare H, X = -CH2-NH-, m=n=l, U is 1,3-benzene, Y=Z= -NH-CH2-, Q is not 2-boronophenyl; and (10) when Ri through Rδ are H, X = -CO-O-, m= 1 and n=0, Q is not 4- methoxyphenyl.
7. A compound described by formula (7):
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM . alkylcarbonyl, -CH=NOH, -CONHOH, -SO3H, -SO2CH3, or -SO2NH2; R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m or n is each independently 0 or 1; x is -CO-O-, -cm-o-co-, -co-NH-,- cm-o-NH-, -cm-cm, -CH=CH-, -cm-
O-, Y is -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, - -NH-Cm-, -CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(CH2), or -(CH=CH)j (wherein i = 0, 1, 2 or 3 and j = 0 or 1), - CHRs- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R2i each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CmCHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, Ci β alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2Nm, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
8. A compound described by formula (8):
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, C alkoxy, RwRisN- (wherein Rw and R15 are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CHs)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, -SO2CH3, or -SO2NH2; R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m or n is each independently 0 or 1; x is -C0-0-, -cm-o-co-, -co-NH-,- cm-o-NH-, -cm-cm, -CH=CH-, -cm-
O-, Y is -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -Cm-O-, -NH-Cm-, -CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or
-N=N-; W is oxygen or lone-pair electrons; U represents -(Cm or -(CH=CH)j (wherein i = 0, 1, 2 or 3 and j = 0 or 1), -CHR9- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10J, a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherem the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CmCHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, Cs-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBFt), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 tlirough R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
9. A compound described by formula (9):
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Rιs and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, -SO2CH3,
1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents a nitrogen, -CHCHs-CH=, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2Nm, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHRuCORι2 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NR19OH (wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or - CHR2oN(COR2i)OH (wherein Ri9 through R21 each independently represents a hydrogen, Ci- β alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-. 10. A compound described by formula (10):
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-e alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Rtβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CHs)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, -SO2CH3, or -SO2Nm; 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -CH=N-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-. Y or Z is not -CO-NH or
V represents a nitrogen, -Cm-CH=, -Cm-Cm-CH=, -CHCHs-CH=, a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, C alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CmNHOH, - C(CHs)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); , P and Q each independently represents -CH2CHR11COR12 or -CHRuCORπ [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein Ri9 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Ri3, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRtsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO- or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, when Ri through Rt represent hydrogen, X is not -NH-CO- or -NH-SO2-.
11. A compound described by formula (11):
wherein Ri through R each independently represents hydrogen, CM alkyl, Gs-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Rιs and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CHs)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, -SO2CH3, or -SO2NH2; 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -CH=N-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents a nitrogen, a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rto, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONRisOH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CmCHRuCORn or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Rtβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or - CHR>oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, O- δ alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, (1) when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-; and (2) when Ri through Rtare H, X = -CH2-NH-, l=m=n=2, V is a nitrogen, Y=Z= -NH-CH2-, P and Q is not 2-boronophenyl at the same time.
12. A compound described by formula (12):
wherein Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), Rι4RιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -C(CHs)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, -SO2CH3, or -SO2Nm; 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -Cm-Cm-CH=, -CHCm-CH=, a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), Rι4RιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH,
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CmCHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, C alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2t)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-.
13. A compound described by formula (13):
wherein Rt and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, -SO2CH3, or -SO2NH2; 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -
N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -Cm-CH=, -Cm-Cm-CH=, -CHCH3-CH=, a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rto, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHRuCORu [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or aheterocyclic alkene may be substituted with one or more substituents R13, and each Ru independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CH3)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci-β alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -CO-NH or -SO2-NH-.
14. A compound described by formula (14):
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, C alkyl or benzyl), RwRιsRiδN+G~ (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CHs)=NOH, -C(OH)=NOH, -CONHOH, -SOsH, -SO2CH3, or -SO2Nm; 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, - CH=CH-, -NH-Cm-, -CH=N-, -CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; V represents a nitrogen, -CH2-CH= , -Cm-Cm-CH=, -CHCH3-CH=, a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -
-C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); P and Q each independently represents -CmCHRιιCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy,
-NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, R14R15N- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes rO-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s); with the proviso that, when P or Q is 3-boronophenyl, Y or Z is not -COJMH or -SO2-NH-. 15. A compound described by formula (15):
wherein Ri and Rz each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen, CM alkyl or benzyl), Rι RιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -C(CH3)=NOH, -C(OH)=NOH, -CONHOH, -SO3H, -SO2CH3, or -SO2NH2; Rs through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl, or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m or n is each independently 0 or 1; x is -C0-0-, -cm-o-co-, -co-NH-,- CH2-0-NH-, -cm-cm, -CH=CH-, -cm-
O-, Y is -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -
-NH-Cm-, -CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(Cm)ι or -(CH=CH)j (wherein i = 0, 1, 2 or 3 and j = 0 or 1), - CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio] , a C5-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents .Rio, and each Rio independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or C alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl,
-CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); Q represents -CmCHRnCORi2or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)J, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, halogen, cyano, acetyl, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NH2, -CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, trifluoromethyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two, or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N or O atom(s).
16. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier. 21. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.
23. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.
24. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable carrier.
25. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier.
27. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable carrier.
30. A pharmaceutical composition comprising the compound of claim 15 and a pharmaceutically acceptable carrier.
31. A method for treating infection caused by coronavirus comprising administering to a subject suffering from such an infection an effective amount of a boron-containing compound.
32. The method of claim 31 where in the boron-containing compound is described by formula (A) HO B OH (A) " 1 wherein Ti comprises a ring structure or any other organic functional group; and B is boron.
33. The method of claim 31 wherein the boron-containing compound is described by formula (B)
wherein Ti and T3 each comprises a ring structure or any other organic functional group; and T2 is a linker.
34. The method of claim 31, wherein th& boron-containing compound is a multifunctional boronic acid.
35. The method of claim 31 , wherein the boron-containing compound is a bi-functional boronic acid.
36. The method of claim 31, wherein the boron-containing compound is described by formula (1)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RtδN+G" (wherein Rw, Ris and Rtβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein Ri9 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -COCK
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(Cm)ι-, -(CH=CH)j-, -(CmcmO)j- or -(CmcmN)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein R17 is hydrogen or CM alkyl), -O(Cm)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3), - CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein R17 is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
37. The method of claim 31, wherein the boron-containing compound is desecribed by formula (2)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -0-cm-, -cm-0-, -NH-cm-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(Cm)i-, -(CH=CH)j-, -(CmcmO)j- or -(CmCmN)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R? represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein R17 is hydrogen or CM alkyl), -O(Cm)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3), - CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CmCHRuCORπ or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRι9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G~ (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein R17 is hydrogen or CM alkyl), - O(Cm ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
38. The method of claim 31, wherein the boron-containing compound is described by formula (3)
Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHRi7 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO- O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(Cm -, -(CmcmO)j- or -(CmcmN)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R> represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rto], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rto, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRtsRt6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CHzNHOH, - C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3), - CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CmCHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein Ri9 represents a hydrogen, CM alkyl, Cs-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORis- (wherein Rts is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(COR2i)OH(wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). 39. The method of claim 31, wherein the boron-containing compound is desecribed by formula (4)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-e alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -Cm-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-Cm-, -Cm-O-, -NH-cm-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, Cs-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR>oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
40. The method of claim 31 , wherein the boron-containing compound is desecribed by formula (5)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm>ORi8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -Cm-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CH2CHR11COR12 or -CHRuCORπ [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBEt), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(CORi9)OH( wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). 41. The method of claim 31, wherein the boron-containing compound is desecribed by formula (6)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -Cm-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-Cm-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CmCHRuCOR or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, C alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONRwOH or - CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or. all three rings contain(s) one or more S, N, O, P or Se atom(s).
42. The method of claim 31, wherein the boron-containing compound is described by formula (7)
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano', borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SO3H,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -Cm-Cm-, -CH=CH-, -O-CH2-, -cm-o-, -NH-Cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(CH2)i-, -(CH=CH)j-, -(CmcmO)j- or -(C CH2N)j- (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(Cm)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein Ri9 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G~ (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONRisOH or - CHR>oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
43. The method of claim 31, wherein the boron-containing compound is desecribed by formula (8)
wherein Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORi8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -Cm-Cm-, -CH=CH-, -O-CH2-, -cm-o-, -NH-Cm-, -CH=N-, - CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(Cm)i-, -(CH=CH)j-, -(CmCmO)j- or -(CmcmN)j- (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Ru and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHRn (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each mdependently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-β alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, Ci-β alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic, one or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
44. The method of claim 31, wherein the boron-containing compound is desecribed by formula (9)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein R14 and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SO3H,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm>ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -Cm-Cm-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-Cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), Rι4Ri5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-e alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRuCORπor -CHRuCORπ [wherein Ru represents Ci-δ alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy,
-NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)] , a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy,- phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHRi7 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
45. The method of claim 31, wherein the boron-containing compound is desecribed by formula (10) wherein Ri through R4 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-e alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein Ri9 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -Cm-Cm-, -CH=CH-, -O-Cm-, -CH2-O-, -NH-CH2-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy^ hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO∑NHRπ (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRnCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy,
-NRi9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each Rn independently represents hydrogen, CM alkyl, Cs-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRiβN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein Ri9 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, herein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
46. The method of claim 31, wherein the boron-containing compound is desecribed by formula (11)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORι8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -cm-cm-, -CH=CH-, -o-cm-, -cm-o-, -NH-cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C=, -Cm-CH=, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORι8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRnCORπor -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy,
-NRt9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
47. The method of claim 31, wherein the boron-containing compound is desecribed by formula (12)
wherein Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -CH2-CH=, -Cm-Cm-CH=, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rto independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, C alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRuCORi∑or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy,
-NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein R14, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONRi9OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s). 48. The method of claim 31, wherein the boron-containing compound is desecribed by formula (13)
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SO3H,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORιs- (wherein Ris is hydrogen or CMS alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -Cm-CH=, -Cm-Cm-CH=, -CHCH3-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, Cs-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NR19OH (wherein Ri9 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a Cs-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents Rι3, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, n-butoxy, t'-butoxy, i'ec-butoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci- e alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH,
-C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, Cs-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
49. The method of claim 31, wherein the boron-containing compound is desecribed by formula (14)
wherein Ri and Rz each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SO3H,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRnCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy,
-NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, n-butoxy, t'-butoxy, sec-butoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci- 6 alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2Cm, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1,
-CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
50. The method of claim 31, wherein the boron-containing compound is desecribed by formula (15)
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SO3H,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORis- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -Cm-Cm-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-Cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(CEfe).-, -(CH=CH)j-, -(CmcmO)j- or -(CmcmN)j- (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein R? represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R10J, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4 orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR7 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen'or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHRzoN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CmCHRuCORi∑or -CHRuCORi∑ [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR>oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
51. The method of claim 31, wherein the coronavirus is a coronavirus having protease(s) that has one or more serine or threonine residue(s) at or near its active site.
52. The method of claim 31, wherein the coronavirus is SARS-associated coronavirus.
53. A method for inhibiting coronavirus protease comprising contacting the coronavirus protease with an effective amount of a boron-containing compound.
54. The method of claim 53 where in the boron-containing compound is described by formula (A) HO B OH (A) wherein Ti comprises a ring structure or any other organic functional group; and B is boron.
55. The method of claim 53 wherein the boron-containing compound is described by formula (B) HO B OH HO B OH (B) wherein Ti and T3 each comprises a ring structure or any other organic functional group; and T2 is a linker.
56. The method of claim 53, wherein the boron-containing compound is a multifunctional boronic acid.
57. The method of claim 53, wherein the boron-containing compound is a bi-functional boronic acid.
58. The method of claim 53, wherein the boron-containing compound is described by formula (1)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G' (wherein Rw*, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs through R8 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO- O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -Cm-O-, -NH-Cm-, - CH=N-,
-Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(Cm)t-, -(CH=CH)j-, -(CmcmO)j- or -(CmCmN)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHR9- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3), - CONR19OH or -CHR2oN(COR>ι)OH( wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CmCHRuCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, C alkoxy, -NRi9OH( wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen.or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci- β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond. One, two or all three rings may be aromatic. One or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
59. The method of claim 53, wherein the boron-containing compound is described by formula (2)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORι8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R> through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -COCK
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(Cm);-, -(CH=CH)j-, -(CmcmO)j- or -(CmcmN)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHRs- [wherein R> represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each ependently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, Ci-β alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3), -CONR19OH or -CHR2oN(COR2i)OH(wherein R19 through Rn each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci- β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
60. The method of claim 53, wherein the boron-containing compound is described by formula (3)
wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORt9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs through Rs each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n are each independently 0, 1, or 2; X and Y each independently represents -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -COCK
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; U represents -(Cm)ι-, -(CH=CH)j-, -(CmcmO)j- or -(CmcmN)j- (wherein i = 0, 1, 2, 3, 4, 5, or 6, and j = 0, 1, or 2), -CHRs- [wherein R9 represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, C alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)jORιs- (wherein Ris is hydrogen or CM alkyl, and j is 1, 2 or 3), - CONR19OH or -CHR2oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rt3, Ru represents hydroxyl, CM alkoxy, -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR>oN(COR2i)OH (wherein R19 through R21 each independently represents a hydrogen, Ci- β alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
61. The method of claim 53, wherein the boron-containing compound is described by formula (4) wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm ORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORt9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -Cm-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-,
-Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CmCHRnCORi2θr -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SO3H, -SO2CH3, -S02NHRn (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
62. The method of claim 53, wherein the boron-containing compound is described by formula (5) wherein Rt through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -Cm-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CmCHRuCORπor -CHRuCORι2 [wherein Rn represents CM alkyl, Cs-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR>oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
63. The method of claim 53, wherein the boron-containing compound is described by formula (6) wherein Ri through Rt each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, R15 and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Rs and Rδ each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, trifluoromethoxy, halogen, acetyl, carboxyl, CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, hydroxymethyl, or formyl; m and n is each independently 0, 1 or 2; X is -O-, -NH-, -S-, -SO2-, -CO-, -Cm-, -CH=CH-CO-O-, -CH=CH-CO-NH-, - CO-O-,
-O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; Q represents -CmCHRuCOR or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, Ci-β alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or Ci-β alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR>oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
64. The method of claim 53, wherein the boron-containing compound is described by formula (7)
wherein Ri and Rz each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-Cm-, -CH=N-, - CH2-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(Cm)ι-, -(CH=CH>, -(CH2CH2O)- or -(CffiCM)- (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRtsN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHRuCORπ [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9θH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each Ri3 independently represents hydrogen, C alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci-β alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=fNOH, - C(OH)=NOH, -SOsH, -SO2Cm, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR>oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
65. The method of claim 53, wherein the boron-containing compound is described by formula (8)
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRt5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -Cm-Cm-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-Cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(CH2)i-, -(CH=CH)j-, -(CmCmO)j- or -(CmcmN)j- (wherein i = 0, 1, /2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHR9- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rto], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G~ (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CmNHOH, - C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or. CM alkyl), -O(Cm>ORi8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CmCHRuCORπor -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, Rι2 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or Ci-β alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherem the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRisRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORi8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHRzoN(CORi9)OH (wherein Ri9 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic, one or more carbon(s) may be attached to oxygen to form -CO-. If the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
66. The method of claim 53, wherein the boron-containing compound is described by formula (9)
wherein Ri through Rt each independently represents hydrogen, Ci-β alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SO3H,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(CH2)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -cm-cm-, -CH=CH-, -o-cm-, -cm-o-, -NH-cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C=, -Cm-CH=, -Cm-Cm-CH=, -CHCm-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or Ci-β alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR>oN(CORi9)OH(wherein R19 and R20 each independently represents a -hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHRuCORi2 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy,
-NRi9OH(wherein Ri9 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)] , a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl),
-O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
67. * The method of claim 53, wherein the boron-containing compound is described by formula (10) wherein Ri through R4 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF ), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -cm-cm-, -CH=CH-, -0-CH2-, -cm-o-, -NH-Cm-, -CH=N-, -
Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C=, -CH2-CH=, -Cm-Cm-CH=, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-C(CHs)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or Ci-e alkyl), -O(Cm)kORι8- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONRi9OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRuCORi∑or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, Ci-β alkoxy, -NR19OH (wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and R15 are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
68. The method of claim 53, wherein the boron-containing compound is described by formula (11)
wherein Ri through R4 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RιβN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, Ci-δ alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m and n is each independently 0, 1 or 2; X, Y and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-, -CO-NH-, -NH-CO-, -cm-cm-, -CH=CH-, -o-cm-, -cm-o-, -NH-cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; V represents nitrogen, -CH=C=, -Cm-CH=, -Cm-Cm-CH=, -CHCH3-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene which may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-C(Cm)=NOH, -C(OH)=NOH, -SO3H, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONRi9OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CmCHRuCORπ or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NR19OH (wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene which may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RtδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -Sθ2NHRn (wherein Rn is hydrogen or CM alkyl),
-O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR_oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
69. The method of claim 53, wherein the boron-containing compound is described by formula (12)
wherein Ri and R2 each independently represents hydrogen, C alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδΝ+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORι9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-Cm-, -Cm-O-, -NH-Cm-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -Cm-CH-, -Cm-Cm-CH=, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH,
-C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or i CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -
CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NR19OH (wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, n-butoxy, z-butoxy, sec-butoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci- β alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
.C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
70. The method of claim 53, wherein the boron-containing compound is described by formula (13)
wherein Ri and R2 each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -Sθ2NHRn (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONRi9OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -Cm-CH=, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CH3)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR.2 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NR19OH (wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH,-C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2Cm, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl),
-O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
71. The method of claim 53, wherein the boron-containing compound is described by formula (14)
wherein Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riβ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SO3H,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); 1, m, and n is each independently 0, 1, or 2; X, Y, and Z is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, - O-CO-, -CO-NH-, -NH-CO-, -CH2-CH2-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-CH2-, - CH=N-, -Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons. V represents nitrogen, -CH=C=, -Cm-CH=, -Cm-Cm-CH=, -CHCHs-CH=, a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(Cm)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein R17 is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONRIΘOH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); P and Q each independently represents -CH2CHR11COR12 or -CHR11COR12 [wherein Rn represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NR19OH (wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein R14 and Ris are each independently hydrogen, hydroxyl or C alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, n-butoxy, t'-butoxy, sec-butoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or Ci- β alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, Sθ4θrBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH,
-C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR>oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
72. The method of claim 53, wherein the boron-containing compound is described by formula (15)
wherein Ri and R> each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, Ci-β alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRi5RiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, -C(CHs)=NOH, -C(OH)=NOH, -SOsH,
-SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); R3 through Re each independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, benzyl or the carbon and attached two Rs, they together form C3-7 cycloalkyl; m and n is each independently 0 or 1; X and Y is each independently -O-, -NH-, -S-, -SO2-, -CO-, -CH2-, -CO-O-, -O- CO-,
-CO-NH-, -NH-CO-, -Cm-Cm-, -CH=CH-, -O-CH2-, -CH2-O-, -NH-Cm-, -CH=N-, - Cm-NH-, -SO2-O-, -O-SO2-, -SO2-NH-, -NH-SO2- or -N=N-; W is oxygen or lone-pair electrons; U represents -(CH2),-, -(CH=CH)j-, -(CmCH2O)j- or -(CmcmN)j- (wherein i = 0, 1, 2, 3, 4, 5 or 6, and j = 0, 1 or 2), -CHRs- [wherein Rs represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rio], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents Rto, and each Rio independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRiδN+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, -CH2COOH, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH=NOH, -CH2NHOH, - C(CHs)=NOH, -C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), -O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), - CONR19OH or -CHR2oN(CORi9)OH(wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); Q represents -CH2CHR11COR12 or -CHR11COR12 [wherein Ru represents CM alkyl, C3-7 cycloalkyl, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or heterocyclic alkene may be substituted with one or more substituents R13, R12 represents hydroxyl, CM alkoxy, -NRi9OH(wherein R19 represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl), RwRisN- (wherein Rw and Ris are each independently hydrogen, hydroxyl or CM alkyl)], a C3-7 cycloalkane, a cyclic alkene or a heterocyclic alkene, wherein the cycloalkane, cyclic alkene or a heterocyclic alkene may be substituted with one or more substituents R13, and each R13 independently represents hydrogen, CM alkyl, C3-7 cycloalkyl, CM alkoxy, RwRisN- (wherein Rw and Ris are each independently hydrogen or CM alkyl), RwRιsRi6N+G" (wherein Rw, Ris and Riδ are each independently hydrogen, CM alkyl or benzyl, G represents halogen, SO4orBF4), trifluoromethyl, trifluoromethoxy, difluoromethoxy, halogen, cyano, borono, nitro, carboxyl, CM alkylcarboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzoyl, benzyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, CM alkylcarbonyl, -CH-NOH, -CH2NHOH, -C(CHs)=NOH, - C(OH)=NOH, -SOsH, -SO2CH3, -SO2NHR17 (wherein Rn is hydrogen or CM alkyl), - O(Cm)kORιs- (wherein Ris is hydrogen or CM alkyl, and k is 1, 2 or 3), -CONR19OH or - CHR_oN(CORi9)OH (wherein R19 and R20 each independently represents a hydrogen, CM alkyl, C3-7 cycloalkyl, trifluoromethyl, phenyl or benzyl); each cyclic alkene is independently a structure containing 1, 2 or 3 rings, each ring containing 5, 6 or 7 carbon atoms and at least one double bond; one, two or all three rings may be aromatic; one or more carbon(s) may be attached to oxygen to form -CO-; if the cyclic alkene contains more than one ring, the ring may be fused, connected by a bond, or connected by a linker L (wherein L includes -O-, -NH-, -S-, -SO2-, -CO-, or -CH2-); and each heterocyclic alkene is independently a cyclic alkene as defined above, wherein one, two, or all three rings contain(s) one or more S, N, O, P or Se atom(s).
73. The method of claim 53, wherein the coronavirus is a coronavirus having protease(s) that has one or more serine or threonine residue(s) at or near its active site.
74. The method of claim 53, wherein the coronavirus is SARS-associated coronavirus.
75. A method for detecting coronavirus in a test sample comprising contacting the sample with an effective amount of a boron-containing compound.
76. The method of claim 75 where in the boron-containing compound is described by formula (A) HO B OH I (A) Ti wherein Ti comprises a ring structure or any other organic functional group; and B is boron.
77. The method of claim 75 wherein the boron-containing compound is described by formula (B)
wherein Ti and T3 each comprises a ring structure or any other organic functional group; and T2 is a linker.
78. The method of claim 75, wherein the boron-containing compound is a multifunctional boronic acid.
79. The method of claim 75, wherein the boron-containing compound is a bi-functional boronic acid.
EP04816955A 2003-10-31 2004-11-01 Inhibitors of coronavirus protease and methods of use thereof Withdrawn EP1682076A4 (en)

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